Developed disease-modifying drugs for AD treatment in clinical trials.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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Many of the traditional farming methods used in the past are still useful today. Organic farming takes the best of these and combines them with modern scientific knowledge. Authors' task was to write a book where many different existing studies could be presented in a single volume, making it easy for the reader to compare methods, results and conclusions. As a result, studies from different countries have been compiled into one book. I believe that the opportunity to compare results and conclusions from different authors will create a new perspective in organic farming and food production. I hope that our book will help researchers and students from all over the world to attain new and interesting results in the field of organic farming and food production.",isbn:"978-953-51-2256-2",printIsbn:null,pdfIsbn:"978-953-51-5423-5",doi:"10.5772/60459",price:139,priceEur:155,priceUsd:179,slug:"organic-farming-a-promising-way-of-food-production",numberOfPages:374,isOpenForSubmission:!1,isInWos:1,hash:"2fc4ebe62bfe43276e05ac2021c624ef",bookSignature:"Petr Konvalina",publishedDate:"March 9th 2016",coverURL:"https://cdn.intechopen.com/books/images_new/5058.jpg",numberOfDownloads:24806,numberOfWosCitations:8,numberOfCrossrefCitations:6,numberOfDimensionsCitations:20,hasAltmetrics:1,numberOfTotalCitations:34,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 4th 2015",dateEndSecondStepPublish:"March 25th 2015",dateEndThirdStepPublish:"June 29th 2015",dateEndFourthStepPublish:"September 27th 2015",dateEndFifthStepPublish:"October 27th 2015",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,editors:[{id:"77330",title:"Dr.",name:"Petr",middleName:null,surname:"Konvalina",slug:"petr-konvalina",fullName:"Petr Konvalina",profilePictureURL:"https://mts.intechopen.com/storage/users/77330/images/3394_n.jpg",biography:"Dr. Petr Konvalina is the vice-dean for external relations at the Faculty of Agriculture, University of South Bohemia in České Budějovice, Czech Republic. He is an Associate professor in plant production. He is oriented towards organic plant production, wheat growing, organic plant breeding and organic food processing. On these topics he has published more than 100 reviewed scientific papers. The papers are mostly focused on the possibilities of practical use of genetic resources of wheat (emmer, einkorn, spelt) in organic farming. Dr. Konvalina has been involved in many national and international research and educational projects related to organic plant production.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"University of South Bohemia in České Budějovice",institutionURL:null,country:{name:"Czech Republic"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"327",title:"Food Safety",slug:"food-safety"}],chapters:[{id:"49291",title:"The Role of Biological Diversity in Agroecosystems and Organic Farming",doi:"10.5772/61353",slug:"the-role-of-biological-diversity-in-agroecosystems-and-organic-farming",totalDownloads:2159,totalCrossrefCites:0,totalDimensionsCites:4,signatures:"Beata Feledyn-Szewczyk, Jan Kuś, Jarosław Stalenga, Adam K.\nBerbeć and Paweł Radzikowski",downloadPdfUrl:"/chapter/pdf-download/49291",previewPdfUrl:"/chapter/pdf-preview/49291",authors:[{id:"170285",title:"Ph.D.",name:"Beata",surname:"Feledyn-Szewczyk",slug:"beata-feledyn-szewczyk",fullName:"Beata Feledyn-Szewczyk"},{id:"170286",title:"Prof.",name:"Kuś",surname:"Jan",slug:"kus-jan",fullName:"Kuś Jan"},{id:"170741",title:"Dr.",name:"Jarosław",surname:"Stalenga",slug:"jaroslaw-stalenga",fullName:"Jarosław Stalenga"},{id:"177309",title:"Mr.",name:"Adam",surname:"Berbeć",slug:"adam-berbec",fullName:"Adam Berbeć"},{id:"177310",title:"MSc.",name:"Paweł",surname:"Radzikowski",slug:"pawel-radzikowski",fullName:"Paweł Radzikowski"}],corrections:null},{id:"49409",title:"Organic Farming as an Essential Tool of the Multifunctional Agriculture",doi:"10.5772/61630",slug:"organic-farming-as-an-essential-tool-of-the-multifunctional-agriculture",totalDownloads:1846,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Elpiniki Skoufogianni, Alexandra Solomou, Aikaterini Molla and\nKonstantinos Martinos",downloadPdfUrl:"/chapter/pdf-download/49409",previewPdfUrl:"/chapter/pdf-preview/49409",authors:[{id:"176054",title:"Dr.",name:"Alexandra",surname:"Solomou",slug:"alexandra-solomou",fullName:"Alexandra Solomou"},{id:"176055",title:"Dr.",name:"Elpiniki",surname:"Skoufogianni",slug:"elpiniki-skoufogianni",fullName:"Elpiniki Skoufogianni"},{id:"176056",title:"BSc.",name:"Konstantinos",surname:"Martinos",slug:"konstantinos-martinos",fullName:"Konstantinos Martinos"},{id:"177635",title:"Dr.",name:"Aikaterini",surname:"Mola",slug:"aikaterini-mola",fullName:"Aikaterini Mola"}],corrections:null},{id:"49429",title:"Pollution Prevention, Best Management Practices, and Conservation",doi:"10.5772/61246",slug:"pollution-prevention-best-management-practices-and-conservation",totalDownloads:1775,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Maliha Sarfraz, Mushtaq Ahmad, Wan Syaidatul Aqma Wan Mohd\nNoor and Muhammad Aqeel Ashraf",downloadPdfUrl:"/chapter/pdf-download/49429",previewPdfUrl:"/chapter/pdf-preview/49429",authors:[{id:"25185",title:"Dr.",name:"Muhammad Aqeel",surname:"Ashraf",slug:"muhammad-aqeel-ashraf",fullName:"Muhammad Aqeel Ashraf"},{id:"58916",title:"Prof.",name:"Dr. Mushtaq",surname:"Ahmad",slug:"dr.-mushtaq-ahmad",fullName:"Dr. Mushtaq Ahmad"},{id:"175806",title:"Dr.",name:"Maliha",surname:"Sarfraz",slug:"maliha-sarfraz",fullName:"Maliha Sarfraz"}],corrections:null},{id:"49166",title:"Organic Weed Control and Cover Crop Residue Integration Impacts on Weed Control, Quality, Yield and Economics in Conservation Tillage Tomato-A Case Study",doi:"10.5772/61315",slug:"organic-weed-control-and-cover-crop-residue-integration-impacts-on-weed-control-quality-yield-and-ec",totalDownloads:1409,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Andrew J. 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Alzheimer’s disease (AD) is the main neurological cause of dementia, and it affects about 46 million people worldwide, mostly elderly adults. The incidence of AD increases exponentially every 5 years from 65 years of age, and it is estimated that 74.7 and 131.5 million people will be living with AD by 2030 and 2050, respectively (World Alzheimer Report, 2015). Patients with AD undergo progressive memory loss, reduced cognitive capacity and eventually, dementia. The debilitating effects of AD, especially at advanced disease stages, impose a substantial financial burden on AD patient’s families, primarily due to the cost associated with medical care. However, the etiology of AD still remains largely unclear and although there has been much effort to elucidate the pathophysiological mechanisms underlying this devastating condition over the last 20 years, the principal cause remains unknown, representing an important unmet clinical need. Therefore, AD is undoubtedly one of today’s most challenging global public health problems, and there is a pressing need to develop novel therapeutic agents to prevent and treat this disease.
\nThe neuropathological hallmarks of AD include the formation of extracellular senile plaques due to the aggregation of amyloid-β (Aβ; normally associated with local inflammation and dystrophy/swelling of neurites), the formation of intracellular neurofibrillary tangles of hyper-phosphorylated tau protein, as well as a loss of synaptic connections and neuronal degeneration [1]. Clinically, AD can be classified into two categories: familial AD (FAD, also known as early-onset AD) and sporadic AD (SAD, also known as late-onset AD). FAD generally accounts for <1% of the total AD cases, and they correspond to a disease variant with onset prior to 65 years of age [2]. This familial form of AD is inherited in an autosomal dominant pattern, and it is caused by mutations in three genes involved in Aβ generation: the amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) [3]. In contrast to FAD, no single gene mutation has been found to be directly responsible for the onset and pathogenesis of SAD [4]. For the late-onset cases, the principal risk factors are ageing and the apolipoprotein E (ApoE) allele ε4 (see Section 3.1.).
\nThe identification of clinical mutations in APP and presenilins in association with FAD has contributed to our understanding of AD pathogenesis. APP is a transmembrane protein that undergoes primary enzymatic cleavage by an α- or β-secretase in its extracellular (or intraluminal) domain, as well as secondary cleavage by a γ-secretase within the transmembrane region (Figure 1). The metalloproteases ADAM10 and/or ADAM17 appear to be responsible for this α-secretase activity and the aspartyl protease BACE-1 (beta-site APP cleaving enzyme 1) corresponds to the β-secretase activity, whereas γ-secretase is an aspartyl proteolytic complex containing four subunits (PS1 or 2, nicastrin, APH1, and PEN-2) [5]. APP cleavage may be produced by β- and γ-secretases in a pathway known as the amyloidogenic route of APP. First, APP β-cleavage produces soluble APP-β (sAPPβ) and a transmembrane C-terminal fragment known as β-CTF or C99. The latter then undergoes γ-secretase cleavage to generate the APP intracellular domain (AICD) and the Aβ peptide, preferentially the Aβ40 and 42 isoforms. Alternatively, APP may be cleaved by α- and γ-secretases in a pathway known as the non-amyloidogenic route of APP where α-secretase cleaves APP right in the middle of the Aβ sequence (Figure 1) to generate soluble APPα (sAPPα) and a transmembrane C-terminal fragment known as α-CTF or C83. The latter undergoes further γ-cleavage to produce AICD and p3 (also known as Aβ17–40/42). In this context, it has been widely reported that FAD mutations induce alterations in APP processing that increased the cellular production of Aβ and augment the Aβ 42/40 ratio. Since mutations in both APP and presenilins are the major causal factors in FAD etiology, altered APP metabolism was assumed to be the principal cause triggering AD, leading to the formulation of the amyloid cascade hypothesis more than 20 years ago. Finally, it is notable that all these participants in APP metabolism, APP and secretases, are membrane-associated proteins influenced by the composition and structure of cell membrane lipids that in turn modulate APP metabolism [6].
\nAPP processing by secretases. In the non-amyloidogenic pathway, APP is first cleaved by α-secretase at a sequence of amino acids within the Aβ peptide, releasing the sAPPα ectodomain. Further processing of the resulting membrane-associated C-terminal C83 fragment (α-CTF) by γ-secretase leads to the release of the p3 fragment and the APP intracellular domain (AICD). This processing takes place preferentially at the plasma membrane. Conversely, the amyloidogenic pathway is initiated when β-secretase cleaves APP at the amino terminus of the Aβ peptide to release the sAPPβ ectodomain. Further processing of the resulting membrane-associated C-terminal C99 fragment (β-CTF) by γ-secretase releases the Aβ peptide and AICD. This processing normally takes place in acidic cellular compartments like late endosomes. The Aβ peptide produced is normally 40 or 42 amino acids long (Aβ40 or 42) and the Aβ42/40 ratio increases in AD.
For more than 20 years, the accumulation of the Aβ peptide has been considered to be the main cellular/molecular event that triggers AD-related neurodegeneration. Amyloid plaques were first thought to cause AD pathogenesis, and more recently, Aβ-soluble oligomers have gained more attention as key players in AD etiology [7]. Regardless of the form of amyloid, the amyloid cascade hypothesis postulates that Aβ accumulation in the brain is the major upstream event in AD pathophysiology, whereas other neuropathological features are a result of this primary amyloid pathology, including the formation of neurofibrillary tangles, neuroinflammation, synaptic failure, and eventually neural death [8, 9].
\nAccording to the amyloid cascade hypothesis, enhanced amyloidogenic activity of secretases and/or reduced clearance of the Aβ peptide may trigger Aβ accumulation. As a result, the secretases involved in Aβ generation have been extensively targeted by the pharmaceutical industry to develop new compounds to treat AD [10]. In particular, the Aβ42/40 ratio may increase due to FAD mutations and this increase enhances oligomer formation, which may in turn impair synaptic function and provoke neuronal degeneration [7]. At the same time, secreted Aβ42 forms primary extracellular Aβ deposits in the brain parenchyma, first as diffuse plaques and later as insoluble fibrillary plaques. A concomitant local inflammatory response develops around these amyloid deposits (involving microglial and astroglial activation), coupled to synaptic spine loss and neurite dystrophy (neuritic pathology) [11, 12]. Over time, these events result in oxidative stress and altered ion homeostasis. Neurofibrillary tangles appear as a consequence of the altered kinase and phosphatase activities that cause tau protein hyperphosphorylation, and likely its subsequent dysfunction in axonal transport, as well as neurite dystrophy [13, 14]. Finally, the cascade ends with extensive synaptic and neuronal dysfunction, which precedes the well-characterized neuronal death associated with the Aβ and tau pathologies [7]. It is this neuronal degeneration that is responsible for memory loss and dementia in patients with AD.
\nAmyloid burden in the brain parenchyma is closely associated with tau hyperphosphorylation, axonal dystrophy and inflammatory reaction around amyloid plaques (Figure 2). Both, inflammation and axonal dystrophy can promote neuronal degeneration [15, 16]. However, it is still largely unknown which of these events (amyloid, inflammation, or neurite dystrophy) appear first during disease development and how these three events are connected. The amyloid cascade hypothesis postulates that amyloid accumulation, first intracellular and then extracellular, leads to the generation of amyloid plaques. Given the close relationship between Aβ plaque number and size with the surrounding dystrophies and gliosis, these two latter events were proposed to progress in conjunction with Aβ plaque formation. However, evidence is now accumulating against the amyloid cascade hypothesis. On the one hand, therapeutic approaches focused on combating amyloid pathology have generally failed to prevent AD progression in clinical trials (see Section 4, [17, 18]), while on the other hand, transgenic AD animal models, mostly created by incorporating human mutated APP and/or PS1 into the animal genome, do not recapitulate all the neuropathological features of AD, and not even the large scale neuronal death that occurs during this pathology [19]. Moreover, the alterations to membrane lipids in neurons of patients with AD suggest that the changes to lipid bilayer could be the first event in the amyloid cascade and related pathways [6]. Indeed, the normalization of membrane lipids is associated with cognitive restoration (see Section 5.2). Accordingly, the amyloid pathology may not actually be the first initial event driving the events that provoke neuronal degeneration.
\nDystrophic neurites surrounding β-amyloid plaques in AD patient’s brain. (a–c) Double-labeling immunofuorescence and confocal microscopy to mitochondrial porin (a; green) and β-amyloid plaques (b; red). Porin immunostaining revealed mitochondrial enrichment in dystrophic neurites surrounding amyloid plaques (c). (d–f) Double-labeling immunofluorescence and confocal microscopy to mitochondrial porin (d; red), and phosphorylated tau (pThr181) (b; green) show co-segregation of porin and hyperphosphorylated tau in dystrophic neurites (long arrow in f). (g–i) Double-labeling immunofuorescence and confocal microscopy to lysosomal associated protein 1 (LAMP-1) (a; green) and mitochondrial porin (b; red). LAMP-1 and porin co-localize in a subset of cellular processes (c; arrowheads) suggesting engulfment of mitochondria into matured autophagic vesicles and participation of lysosomes in its degradation in distrophic neurites. β-Amyloid is stained in blue. Bar 10 μm (a–c and d–f), and 20 μm (g–i). Adapted from [12] with permission of Springer.
It also appears that axon swelling or dystrophy can precede extracellular amyloid deposition in certain animal models, in which autophagic vesicles with all the necessary enzymatic machinery to produce the Aβ peptide are evident [20–23]. In this sense, dystrophic axons have been proposed to be an intracellular source of secreted Aβ that would seed extracellular amyloid plaques. Protein deposits containing APP fragments can be seen in the brain parenchyma of aged wild-type mice, originating from axonal varicosities, further supporting this hypothesis. These data suggest that axonal dystrophy occurs first, leading thereafter to extracellular amyloid deposition in the early stages of the disease. In fact, it has been proposed that neurite dystrophy could reflect a conserved neuroprotective strategy to overcome the age-related accumulation of misfolded proteins, which in turn may represent a molecular mechanism of Aβ plaque deposition that potentially underlies the shift from normal to pathological aging [24, 25]. Nevertheless, Aβ alone may promote axonal atrophy through its interactions with the p75 neurotrophin receptor (p75NTR) in axon membranes [26]. Together, the evidence suggests that dystrophy and extracellular Aβ deposition are involved in a positive feedback loop whereby axon dystrophy is a source of extracellular Aβ, and the latter promotes axonal atrophy.
\nIn terms of neuroinflammation, it is widely accepted that Aβ deposition alone might be sufficient to induce an inflammatory reaction that subsequently contributes to neuronal death and cognitive decline in AD [15]. However, this fact does not necessarily imply that Aβ plaque formation precedes microglial activation in AD. During normal aging, microglial activation aims to clear the misfolded proteins contained in fragmented neurites and aggregated into senile plaques. Interestingly, during AD-related pathological ageing, microglia cells recruited around plaques phagocytose Aβ and this could constitute part of the microglial mechanism to clear misfolded proteins, also during normal ageing [25]. Thus, in a scenario characterized by age-related chronic inflammation, microglia would be highly responsive to further activation which would drive their differentiation toward a classic phenotype characterized by pro-inflammatory cytokine secretion, in turn impairing axon trafficking, promoting Aβ accumulation and cell death [25, 27]. However, this putative role for AD-associated neuroinflammation is not supported by evidence showing that the inflammatory response is not neurotoxic and, indeed, it is even neuroprotective in a transgenic mouse model of AD [28]. In fact, from early in the amyloid pathology, alternative neuroprotective microglia are activated around amyloid plaques supporting neuronal survival, and this alternative phenotype is also present during animal ageing. By contrast, the classic microglial phenotype that is characterized by cytotoxic cytokine secretion only appears at advanced ages, associated with the presence of soluble Aβ oligomers and neuronal loss [27, 28]. Thus, these evidences show that alternative neuroprotective microglia may be present at advanced ages and coexist with classic microglial activation. In summary, although it is widely accepted that neuroinflammation promotes neuronal degeneration, it remains unclear how brain inflammation participates in the shift from normal to pathological ageing.
\nHence, determining whether amyloid pathology is the first event in the pathway to AD-associated neuronal degeneration and dementia appears to be a particularly relevant issue, especially after the repeated fiascos in clinical trials of drugs targeting Aβ and related molecular entities. There is a close relationship among Aβ, inflammatory and neurite pathologies in AD because they all appear at early stages of the disease and all three are involved in neuronal death. In the present chapter, we will review how these neuropathological hallmarks are related to AD-associated membrane lipid alterations, as there can now be no shadow of doubt that brain lipids and the pathways they are involved in influence the pathophysiology of AD.
\nThe amyloid cascade hypothesis was postulated because FAD mutations cause Alzheimer’s disease, and they induce abnormal APP processing that leads to the well-characterized amyloid pathology [9]. Since the pathological hallmarks are exactly the same for both FAD and SAD, the same cascade of neuropathological events is thought to occur in both these disease variants. However, in addition to the influence of FAD clinical mutations on APP metabolism, these mutations may also have additional effects on other signaling cascades. In fact, presenilins (PSs) are the catalytic center of the γ-secretase complex, which cleaves more than 60 type I membrane proteins (one type of single transmembrane spanning region in integral proteins) [29, 30]. More than 160 clinical mutations have been described for PS1 and most of those that were studied induce loss of function of γ-secretase activity [31, 32]. These mutations may exert additional effects on cellular signaling as a consequence of the altered processing of certain membrane proteins that could influence lipid cellular homeostasis. Interestingly, γ-secretase loss of function induced by the ablation of PSs or by transgenic expression of PS1 mutants provoked a severe imbalance in the cholesterol content of the plasma membrane and intracellular membranes [33, 34]. In this sense, PS ablation increased the overall levels of cholesterol and sphingomyelin (SM) in cells, whereas the local concentration of cholesterol at the plasma membrane was dramatically reduced, resulting in the intracellular accumulation of cholesterol and cholesterol-rich membrane domains, such as lipid rafts [33, 34]. These observations demonstrate the impact of γ-secretase loss of function on the cell membrane lipid composition.
\nIn the human brain, cholesterol is mainly transported in lipoprotein particles that predominantly contain ApoE. Interestingly, ApoE has been identified as a risk factor for SAD suggesting that altered cholesterol transport might also be related to the pathogenesis of late-onset AD [35]. The human ApoE protein is comprised of 299 amino acids and it has three isoforms, namely ApoE2, ApoE3, and ApoE4. The differences between these three isoforms lie in the amino acid residues at positions 112 and 158: ApoE2 (Cys112, Cys158), ApoE3 (Cys112, Arg158), and ApoE4 (Arg112, Arg158). In particular, subjects carrying the ApoE4 allele have a 3- to 4-fold higher risk of developing AD than those who do not carry this allele. Furthermore, ApoE4 was observed to exhibit a gene dose–effect, such that individuals who carry two copies of this allele have an even higher risk of suffering AD and an earlier age of onset. The effects of the ApoE4 isoform on AD risk are maximal between the ages of 60 and 70 years old, ApoE4 allele being present in more than 50% of all AD cases. Conversely, ApoE2 carriers appear to be somewhat protected from AD compared with ApoE3 carriers [36]. In this context, the ApoE4 isoform is less efficient in promoting cholesterol flux in neurons and astrocytes, and it also compromises cell uptake of cholesterol-containing lipoproteins compared with the other ApoE isoforms [37]. Furthermore, individuals carrying the ApoE4 allele accumulate less ApoE lipoprotein in the brain than non-ApoE4 carriers [38]. Hence, the expression of ApoE4 in SAD cases appears to alter cholesterol homeostasis in neurons in a similar way as that induced by γ-secretase loss-of-function in PS1-deficient cells and transgenic models of AD harboring clinical PS1 mutations [33, 34]. In such AD models, the loss of γ-secretase activity leads to impaired uptake of lipoproteins from the extracellular media due to the poor internalization of ApoE receptors like the LDLR (low-density lipoprotein receptor) [34]. In AD patients with the ApoE4 allele, cholesterol uptake would be impaired due to the lower affinity of ApoE4 to bind neuronal lipoprotein receptors, and to the lower concentration of circulating ApoE than in individuals carrying the ApoE2 or ApoE3 alleles [38, 39]. In any case, poorer membrane incorporation of neuronal cholesterol leads to increased de novo cholesterol synthesis and an altered neuronal distribution. Thus, altered cholesterol homeostasis is a key aspect of AD pathogenesis and alterations to cholesterol may represent a meeting point in the pathogenesis of FAD and SAD, driving the same neuropathological events in both disease variants, such as increased amyloidogenic APP processing.
\nThe central nervous system (CNS) contains around 25% of the cholesterol in the body and evidence is accumulating that cholesterol homeostasis is indeed associated with AD pathogenesis. High cholesterol and high-density lipoprotein (HDL) in blood plasma are correlated with Aβ load in the brains of patients with AD [40, 41] and that increased cholesterol levels are associated with the incidence of AD [42, 43]. Furthermore, high or low cholesterol levels have often been related to enhanced or diminished Aβ production, respectively, in cell and animal models of AD, although these results are a little controversial [42, 44, 45]. What is more, lipidomic studies have shown that levels of cholesterol, certain cholesterol esters, and certain SM species are upregulated in the brain of patients with AD. This correlation is particularly strong in the case of patients with AD harboring the ApoE4 allele, although some contradictory results have also been reported in this respect [46–49]. Finally, altered cholesterol distribution and transport have been causally linked to neurodegenerative diseases in addition to AD, such as Huntington’s and Niemann–Pick Type C diseases [44].
\nCholesterol is an essential structural component of cell membranes and one of the major components of the functional membrane microdomains known as lipid rafts, together with sphingolipids such as SM and gangliosides. These microdomains are highly ordered membrane structures that serve as platforms for cell signaling, ligand-receptor binding, protein sorting, and other activities in the cell. Interestingly, amyloidogenic APP processing and Aβ aggregation have been proposed to take place in lipid rafts [50]. In fact, the activities of both BACE-1 and γ-secretase are enhanced in this type of membrane microdomains [51, 52]. In this context, compelling evidence supports the involvement of cholesterol and sphingolipids in the amyloidogenic processing of APP. On the one hand, membrane enrichment of these lipids could alter the biophysical properties of the lipid bilayer, affecting secretase activity in a manner that leads to the production of the longer pathogenic Aβ peptides instead of the shorter p3 peptide [53] (see Figure 1). On the other hand, cholesterol and SM storage disorders impair intracellular trafficking of APP, resulting in the accumulation of APP, APP-CTFs, and Aβ in autophagic vesicles of the endolysosomal pathway [54, 55]. Accordingly, impaired distribution of cholesterol and SM is accompanied by the downregulation of proteins involved in endosomal redistribution and fusion to the plasma membrane (SNAREs and RABs) in PS1-deficient cells [33]. These evidences suggest that dysfunctional vesicular trafficking between the plasma membrane and intracellular compartments may be caused by membrane lipid alterations that lead to the neuritic pathology and altered APP processing in FAD transgenic models [33, 56]. Additional studies have also linked shingolipid lysosomal accumulation to autophagic dysfunction and dystrophic neurite formation in AD [55, 57]. Such results indicate that cellular accumulation of sphingolipids could induce key cytopathological changes characteristic of AD, such as alterations to the autophagic/lysosomal system, increased generation of Aβ and accumulation of APP-CTFs in autophagic vesicles at dystrophic neurites, as occurs in an age-dependent manner in transgenic mouse models of AD [58]. Interestingly, a cholesterol-enriched diet in healthy mice also leads to insulin-like growth factor 1 (IGF1) impairment and insulin-mediated pro-survival signaling, which in turn promotes tau hyperphosphorylation in neurons [59]. Together, this evidence suggests that altered cholesterol/sphingolipid homeostasis may promote the neurite pathology, tau hyperphosphorylation, and amyloidogenic APP processing in AD.
\nNevertheless, it cannot be ruled out that AD-related membrane lipid alterations can also potentiate the neurotoxicity of the Aβ oligomers in AD patient’s brains. In fact, lipid rafts may serve as a platform for the cellular interactions with soluble Aβ oligomers, in turn promoting tau hyperphosphorylation and inhibiting synaptic plasticity by hindering LTP (long-term potentiation) in the brain [60, 61]. Moreover, raft-associated lipids such as cholesterol, SM, and the GM1 ganglioside revert the fibrillar Aβ into soluble oligomers, such that altered cellular lipid homeostasis may actually potentiate the severity of the amyloid pathology in AD [62].
\nPolyunsaturated fatty acids (PUFAs) are those fatty acids that contain more than one double bond in their backbone. They are abundant in cell membranes, and they are mainly incorporated into membrane phospholipids. The carbon next to the carboxyl group is known as the α carbon, the next one is the β carbon, and so forth, until the final carbon called the ω carbon. Thus, ω-3 fatty acids have the first double bond between the third and fourth C atoms from the ω carbon. For instance, 22:6 ω-3 or 22:6 n-3 (docosahexaenoic acid, DHA) indicates a 22-carbon chain with six double bonds and with the first double bond between the third and fourth carbons from the CH3 end. The physiological properties of unsaturated fatty acids largely depend on the position of the first unsaturation relative to the end position. The essential fatty acids α-linolenic acid (ALA, 18:3 ω-3) and linoleic acid (LA, 18:2 ω-6) must be incorporated through the diet, and they are the starting point for the synthesis of longer and more unsaturated PUFAs such as arachidonic acid (ARA, 20:4 ω-6), eicosapentaenoic acid (EPA, 20:5 ω-3), and DHA (22:6 ω-3). However, conversion of ALA to longer PUFAs in humans is very inefficient and therefore, these long PUFAs are normally incorporated through the diet, particularly through fish intake [63].
\nThe membranes of the cells in the brain are rich in ω-3 PUFAs such as DHA and EPA. Since AD is a cognitive disorder and DHA is involved in normal cognitive development, the DHA levels in the AD brain have been analyzed extensively. As a result, it is widely accepted that in the human brain AD courses with diminished DHA levels, although a number of discrepancies in this respect have also been observed [64]. These discrepancies may reflect the brain region studied as the neurodegeneration associated with AD does not affect all brain areas homogeneously. In the hippocampus, one of the regions primarily affected in AD, decreased DHA levels are associated with reduced levels of PE (phosphatidylethanolamine) or PE plasmalogens [65–69], supporting a relationship between lower DHA levels and cognitive decline in AD. Moreover, there is significant experimental evidence in animal models that hippocampal DHA deficiency or enrichment is associated with reduced or increased learning memory abilities, respectively [70]. At the cellular level, exposure to ω-3 PUFAs enhances synaptic plasticity by increasing LTP and synaptic protein expression, in turn leading to increased dendritic spine density and hippocampal neurogenesis. In addition, ω-3 PUFAs have antioxidant, anti-inflammatory, and anti-apoptotic effects, thereby promoting neuronal survival during normal ageing and in AD. On the other hand, PUFA deficits are related to enhanced amyloidogenic APP processing and cell susceptibility to Aβ neurotoxicity, particularly as ω-3 PUFA deficiency downregulates neuroprotective signaling (e.g., ERK signaling). Therefore, PUFA deficits may enhance neuron degeneration and cognitive impairment in AD [71].
\nIt still remains largely unclear how ω-3 PUFAs exert their cellular functions and consequently, what signaling cascades are impaired in the brain due to their deficiency. Such ω-3 PUFAs maintain the structural functionality of neural cell membranes. Indeed, in consonance with the reduced levels of DHA in the human AD brain, lipid rafts obtained from AD brain cortex also exhibited significantly less DHA than age-matched controls [72]. Interestingly, the biophysical and structural properties of PE and DHA in membranes are opposed to those of cholesterol and SM. Thus, these abnormalities in lipid raft composition may provoke strong modifications to the membrane structure of neurons such as alteration of membrane viscosity, rigidity and thickness, lateral lipid packing, lipid order, and other parameters, which could in turn be relevant to secretase activity and the production of Aβ [73]. Accordingly, decreased PUFA levels in lipid rafts would be coupled to enriched cholesterol and sphingolipids, thereby promoting the detrimental effects on neurons including the neurite dystrophy, tau hyperphosphorylation, and amyloidogenic APP processing that drives neuronal degeneration (see Section 3.1.).
\nAlternatively, DHA may be released from phospholipids due to the activity of PLA2 (phospholipase A2), acting as a signaling molecule, and DHA can be hydroxylated to produce several secondary bioactive lipids such as resolvins (RVs) and protectins. DHA hydroxylation is mediated through lipoxygenase-15 (LOX-15) or acetylated cyclooxygenase-2 (COX-2) [63]. Compounds derived from DHA are classified as D-series RVs or protectins, while those formed from EPA are designated as E-series RVs. DHA can be hydroxylated on carbon 17 by 15-LOX or acetylated COX-2, leading to stereoselective formation of 17S- or 17R-hydroxy-DHA (17-HDHA), respectively. These derivatives may be further hydroxylated to give rise to trihydroxy derivatives such as the D1, D2, D3, and D4 17-(S/R)-RVs (D-series RVs), and the dihydroxy 17-(R)- and 17(S)-protectin, the latter also known as neuroprotectin D1 (NPD1). EPA can be stereoselectively hydroxylated to 18-(S/R)-hydroxy-EPA (18-HEPA) by cytochrome P450 or acetylated COX-2, which is further processed to form E1, E2 and E3 18-(S/R)-RVs (E-series RVs: Figure 3). Both, 17-HDHA and 18-HEPA serve as markers for RVs and protectins, and remarkably, their presence in blood is directly related to the intake of ω-3 PUFAs in animal models [74]. In addition, these PUFA derivatives are thought to exert their biological function by mechanisms that go beyond the simple regulation of lipid membrane composition and structure. In fact, non-esterified DHA, RVs and protectins may bind to different fatty acid (FA) receptors such as the retinoid X receptor (RXR), G protein-coupled receptors (GPCRs), peroxisome proliferator-activated receptors (PPARs), and fatty-acid binding proteins (FABPs). Although the exact signaling cascade mediated by many of these proteins has not been identified, the mechanism of action of DHA or HDHA derivatives like NPD1 has been proposed to involve PPARγ activation. Indeed, NPD1 is known to promote PPARγ activation more intensely than DHA and as such, the neuroprotective effects of DHA may be mediated by NPD1 and/or other DHA-derived hydroxylated bioactive derivatives in the brain [75, 76].
\nChemical structure of specialized pro-resolving mediators derived from DHA and EPA ω-3 fatty acids. DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) may be released from phospholipids through PLA2 (phospholipase A2) activity and converted into bioactive hydroxylated fatty acids with potent anti-inflammatory properties, known as resolvins and protectins. This conversion may be mediated by several enzymes, including lipoxygenase-15 (LOX-15), acetylated cyclooxigenase-2 (COX-2), and cytochrome P450. Compounds derived from DHA are classified as D-series resolvins (RVs: left panel), while those formed from EPA are designated as E-series resolvins (right panel). Although resolvins normally includes trihydroxy fatty acids, DHA can be also transformed into dihydroxylated compounds denominated as protectins. Within this group, neuroprotectin D1 (NPD1: see left panel) is the best studied DHA-derived hydroxylated compound in terms of AD therapy, and it displays anti-inflammatory, anti-apoptotic, and anti-amyloidogenic properties.
The balance between ω-6 to ω-3 intake has a strong impact on brain health. In Western diets, this ratio is about 10–20:1, while in other cultures and also historically, this ratio has been as low as 1–2:1. Total fat intake as well as the ω-6 to ω-3 ratio in Western diets has increased significantly since the Industrial Revolution, indicating that Western diets are deficient in ω-3 PUFAs [77]. Epidemiological studies, including correlational studies and migration studies, suggest a protective effect against AD of ω-3 PUFAs and fish oil (an important source of ω-3 PUFAs), such that the role of nutrition in preventing AD arouses increasing hope, particularly with reference to ω-3 PUFA dietary intake. One recent meta-analysis reviewed a total of six cohort studies performed in the USA and Europe to address how dietary intake of long-chain ω-3 PUFAs or fish correlates with the incidence of dementia and AD [78]. This meta-analysis found a significant lower risk of AD associated with high fish intake. Such an association was most pronounced when the follow-up period was at least five years and fish intake was 500 g or more per week, such that fish consumption is inversely correlated with AD incidence in a temporal and quantitative manner. A dose–response meta-analysis also showed that for every 100 g per week dietary fish intake the risk of AD falls 11%. This neuroprotective effect of fish intake was mainly attributed to its high long-chain ω-3 PUFA content, particularly DHA [79]. Interestingly, the same meta-analysis also revealed that dietary intake of ω-3 PUFAs alone (not linked to fish consumption) did not lower the risk of dementia or AD. Moreover, an earlier randomized trial reached the same conclusions in patients with mild-to-moderate AD who were administered DHA [80]. Nevertheless, most of the individual studies evaluating the relationships between ω-3 PUFA intake and AD risk suggest there is a potential protective effect of these long ω-3 PUFAs on the incidence of AD, although no significant statistical differences were reached in the pooled analysis.
\nThe discrepancies between fish and ω-3 PUFA consumption in relation to AD incidence may be explained by different factors in terms of the dietary composition or socioeconomic status of the individual. In this context, dietary intake of long-chain ω-3 PUFAs may also be accompanied by the intake of other saturated fats, which would attenuate the neuroprotective effect of ω-3 PUFAs. Alternatively, fish is also a good source of vitamins, essential amino acids and other nutrients, which could in turn be responsible for the beneficial effect attributed to fish in AD prevention. The fact that DHA is converted into bioactive derivatives that mediate its beneficial effects in CNS cannot be overlooked. In this context, the neuroprotective effect of fish intake could be also attributed to PUFA derivatives present in fish, such as hydroxylated forms of PUFAs or PUFA forms easily transformable into bioactive derivatives similar to NPD1 [81]. In fact, fish oil consumption has recently been related to increased levels of total DHA and NPD1-like derivatives in the mouse brain, without any modification of free (unesterified) DHA levels [82]. Hence, fish oil intake promotes elevated levels of NPD1 without affecting basal levels of free DHA in the brain. These data bring to light a central role for ω-3 PUFA hydroxylated bioactive derivatives in the prevention and treatment of AD (see Section 5.2.).
\nModern lipidomic analysis allows a comprehensive atlas to be built up of all the lipid alterations existing in the AD brain. Current laboratory techniques, such as ultra/high pressure liquid chromatography (U/HPLC) and gas chromatography (GC) coupled to mass spectrometry (MS) allow the vast majority of lipids in cells and animal tissues to be studied. Since the brain is the most lipid-enriched organ in the human body, after adipose tissue, alterations in lipid composition might be involved in many neurological disorders, including AD [44]. An in-depth lipidomic analysis performed in the postmortem brain of patients with AD showed heterogeneous changes in lipid metabolism in AD-affected patients [47]. As expected, the cerebellum lipid profile was largely unaffected whereas significant lipid changes were observed in the prefrontal and entorhinal cortex of AD brains when compared with age-matched controls. These changes demonstrate that lipid alterations are restricted to AD-affected brain regions (principally the cortex and hippocampus) and that they are not present in unaffected regions like the cerebellum. Interestingly, the prefrontal cortex displays more severe lipid alterations, with a decrease in PE, LPC (lyso-phosphatidylcholine), and sulfatides, together with elevated levels of ceramides (including glucosyl- and galactosyl-ceramides, Cer) and DAG (diacylglycerol). By contrast, in the entorhinal cortex, significant increases are only evident in LBPA (lysobiphosphatidic acid), SM, ganglioside GM3, and cholesterol esters (ChoE). In addition, polyunsaturated PE 40:6, 38:6, and 38:4 species were markedly downregulated in the prefrontal cortex, whereas there was a general decrease in long-chain fatty acids (≥40C) and a corresponding increase in short-chain fatty acids (≤34C) that is compatible with the lower levels of PE carrying DHA in the brain of patients with AD. Unexpectedly, the entorhinal cortex displays more species of the polyunsaturated lipid pools in PC (phosphatidylcholine) and PE. The different lipid alterations between these two brain regions may reflect different aspects or stages of AD pathophysiology, since the entorhinal cortex is known to be affected earlier and more severely than neocortical areas [83].
\nAD progresses from a pre-symptomatic stage to mild cognitive impairment (MCI), mild AD and to severe AD with a gradual deterioration in cognitive abilities. Unfortunately, the clinical manifestation of the disease is preceded by a long prodromal phase, during which neuropathological lesions arise, including neuron death. For this reason, clinical diagnosis of AD is unreliable, particularly at early disease stages. Hence, there is a strong need to find peripheral biomarkers to reliably diagnose AD early, thereby enabling early treatment and better therapeutic efficacy. Most approaches to fluid-based biomarker discovery have focused on Aβ42, total tau and phosphorylated tau in cerebrospinal fluid (CSF). Although these are useful to distinguish symptomatic patients from normal controls or other dementias, these CSF biomarkers lack predictive value in preclinical patients, and they are only useful to confirm the clinical diagnosis [84]. Thus, given the brain lipid alterations in AD, lipidomic analysis of lipid derivatives in biological fluids may represent a reliable way to identify non-invasive biomarkers for early AD diagnosis [85].
\nOf the lipid changes reported in the CSF, plasma, and serum of patients with AD, many do not necessarily correlate with those described previously in the CNS [6]. For instance, free cholesterol and ChoE were reported to be downregulated in the CSF although they are increased in the brain of patients with AD [86] (see Section 3.1.). However, six different long-chain ChoE species in plasma allowed patients with AD to be accurately discriminated from healthy controls (ChoE 32:0, 34:0, 34:6, 32:4, 33:6, and 40:4). These metabolites accumulated more strongly in healthy controls than in MCI, and in MCI than in AD, such that they were proposed as potential biomarkers for early AD diagnosis [87]. Total PC levels and specific PC species have also been proposed as reliable biomarkers, with diminished PC levels in the CSF of patients with AD accompanied by lowered LPC and increased PC hydrolytic products such as glycerophosphocholine and phosphocholine, suggesting that PC breakdown might be enhanced in AD pathogenesis [88]. Notably, a set of 10 PC metabolites was specifically depleted in the plasma of healthy individuals who later suffered phenoconversion towards MCI/AD. These subjects were diagnosed as AD during a 5-year follow-up even though they displayed no cognitive impairment at entry. The PC species identified were diacyl PC 36:6, 38:0, 38:6, 40:1, 40:2, 40:6, PC acyl-alkyl 40:6, and LPC 18:2, as well as the acylcarnitines (ACs) propionyl AC (C3), and C16:1-OH [89]. It is noteworthy that control subjects (not previously diagnosed with AD) did not display any of these modifications, while already diagnosed patients with AD also showed decreased levels of these PC species. Moreover, downregulation of this panel of lipids predicted phenoconversion from healthy to MCI/AD within a 2–3 year time frame with 90% accuracy [89]. These data were supported by independent studies showing decreased levels of PC 38:4, 38:6, and 40:6 in the plasma or serum of AD subjects [86, 90]. In addition, a variety of peripheral lipid changes were also reported that might potentially be useful for early AD diagnosis, such as lower levels of SM and increased levels of Cers in the plasma or serum of patients with AD. In particular, there were significantly fewer SM species containing long chains (e.g., 22 and 24 carbon atom acyl chains) in AD subjects [86, 91]. In parallel, increased Cer levels were reported in the plasma of patients with AD [91, 92]. SM can be metabolized into Cers, second messengers that regulate cellular differentiation, proliferation and apoptosis. Upregulated levels of Cers were concomitant with significant reductions in SM in the plasma of patients with AD. A correlation between the decrease in SM and the increase in Cers was particularly robust in the ratios of SM and Cer species with identical fatty acyl chains. Cer alterations were particularly evident in mild-to-moderate stages of AD [91]. Moreover, it is noteworthy that upregulated Cer levels were significantly correlated with the onset of memory impairment, supporting the role of Cers as potential AD biomarkers [92].
\nIn conclusion, a wide range of peripheral fluid changes have been described that could be used as biomarkers for early AD diagnosis. However, many of the clinical studies involved are cross-sectional in nature and some of them do not reveal reliable biomarkers to test disease progression. Nevertheless, longitudinal studies with several years of follow-up do identify promising biomarkers for early AD diagnosis that reliably predict cognitive impairment and the onset of AD.
\nThe main risk factors for dementia are age and genetics (see more information about AD risk factors at http://www.alz.org/alzheimers_disease_causes_risk_factors.asp), although other risk factors may also influence the onset of dementia. For instance, since the brain is nourished by a rich network of blood vessels, cardiovascular alterations are considered a risk factor for neurological disorders. In fact, vascular dementia is linked to morphological changes to blood vessels which are in turn present in other types of dementia like AD. Indeed, a healthy cardiovascular system is frequently linked to brain protection [93]. In this context, the control of blood cholesterol levels, blood pressure, and body weight is recommended to maintain good brain health. In fact, high-fat diets and sedentary lifestyles are becoming major concerns in terms of their contribution to the high incidence of dementia in Western society, whereas regular physical exercise and heart-healthy diets are also good habits to lower the risk of dementia [35].
\nOnly two types of drugs are currently available to treat Alzheimer’s disease: acetylcholinesterase inhibitors (often shortened to just “cholinesterase inhibitors”) and NMDA receptor antagonists. Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) bind to and reversibly inactivate cholinesterases, inhibiting acetylcholine hydrolysis. Such inhibition results in increased acetylcholine concentrations at cholinergic synapses and indeed, AD involves a substantial loss of cholinergic neurons in the neocortex and hippocampus, which in turn contributes to the AD symptomatology and to memory impairment in particular. Therefore, increased levels of acetylcholine are thought to protect against the death of cholinergic neurons, alleviating AD symptoms [94]. Memantine is a low-affinity voltage-dependent antagonist of glutamatergic NMDA receptors. By binding to the NMDA receptor, memantine inhibits the sustained influx of Ca2+ ions from the extracellular milieu, thereby preventing neuronal death by excitotoxicity. Such a pathogenic mechanism can be mediated by the Aβ oligomers that bind to NMDA receptor as agonists, favoring Ca2+ influx and neuronal excitotoxicity [95]. Interestingly, memantine preserves physiological receptor activity, such that released glutamate can still mediate receptor activation leading to neuronal depolarization in postsynaptic neurons [96]. However, neither cholinesterase inhibitors nor NMDA antagonists have disease-modifying effects in AD and they are generally viewed as palliative treatments with marginal to minimal clinical efficacy, either alone or in combination. Therefore, only a small percentage of patients with AD respond to these treatments and these responders normally undergo a short period of cognitive stabilization after which they again suffer from the cognitive decline associated to largescale neuronal degeneration [97, 98]. This scenario highlights the unmet clinical need for the treatment of AD and related conditions.
\nDeveloping disease-modifying drugs (DMDs) capable of preventing neuron degeneration and thereby counteracting AD progression is one of the most pressing challenges of modern pharmacology. Since the pathological process of AD begins many years before its clinical diagnosis, the optimal time for a disease-modifying therapy may be during the prodromal stage of AD. Therefore, clinical diagnosis of AD must be achieved when patients show no relevant clinical signs. Indeed, the development of DMDs will require the concomitant incorporation of reliable biomarkers to identify early stages of AD (see Section 3.3). Hitherto, no DMDs are available for AD and although several have been tested up to phase 3, none has yet achieved marketing approval. The recurrent failures in clinical trials raise a number of questions about our understanding of AD pathophysiology. In this sense, the amyloid cascade hypothesis has not only influenced the study of AD pathophysiology over the past 2 decades but also, the choice of drug targets (see Section 2). Therefore, most clinical trials have set out to prevent Aβ accumulation, either by inhibiting its production/aggregation or enhancing its clearance, as well as reducing tau phosphorylation [99, 100]. However, it remains unclear if these two hallmarks of AD are a cause or consequence of the disease. In fact, they could lie downstream of previous molecular/cellular alterations, as a result of the disease pathology (damage response proteins) and/or as products of an endogenous protective response to disease-induced damage. Nonetheless, over the past 20 years the main focus of biomedical research and the associated drug discovery programs for AD have targeted brain amyloid or tau hyperphosphorylation, and the associated formation of neurofibrillary tangles [18].
\nMutations in the BACE-1 gene have not been related to AD but elevated levels of this enzyme have consistently been found in both the brain and CSF of patients with AD [101–103]. Since β-secretase activity is pathologically elevated in AD, BACE1 inhibition has been addressed as a potential therapeutic approach to combat AD. In fact, both genetic deletion of BACE-1 and administration of a BACE-1 inhibitor rescued cognitive deficits and lowered brain Aβ production in AD mouse models. Interestingly, although BACE-1 has other substrates, its inhibition was apparently free of side effects in AD mice [104, 105]. The latest generation of small molecule BACE-1 inhibitors has achieved satisfactory brain penetration and a robust reduction in cerebral Aβ in preclinical animal models. Furthermore, administration of most of these inhibitors in humans also reduced Aβ and sAPPβ levels, whereas sAPPα (the α-secretase cleavage product) was enhanced in the CSF. This observation is consistent with BACE-1 inhibition since β- and α-secretase compete for APP processing (see Figure 1). Many of these BACE-1 inhibitors are still in phase-1 clinical trials where safety and tolerability are tested but some of them are currently in phase 2/3, although no clinical efficacy data are as yet available (Table 1). Interestingly, one such drug (LY2886721 from Eli Lilly Company) was discontinued in a phase-2 trial because a number of subjects developed hepatic toxicity, although they were not associated with the mechanism of action of BACE1 [106].
\nDrug | \nSynonyms | \nCompany | \nMechanism of action | \nResult of study | \nClinical trial ID* | \nObservations | \n
---|---|---|---|---|---|---|
LY2886721 | \n– | \nEli Lilly & Co. | \nβ-Secretase inhibitor | \nDiscontinued in phase 2 | \nNCT01561430 | \nAltered liver biochemistry | \n
AZD3293 | \nLY3314814 | \nAstra Zeneca/ Eli Lilly & Co. | \nβ-Secretase inhibitor | \nOngoing in phase 2/3 | \nNCT02245737 | \n– | \n
Verubecestat | \nMK-8931 MK-8931-009 | \nMerck | \nβ-Secretase inhibitor | \nOngoing in phase 2/3 | \nNCT01739348 NCT01953601 | \n– | \n
E2609 | \n– | \nEisai/Biogen Idec | \nβ-secretase inhibitor | \nOngoing in phase 2 | \nNCT02322021 | \n– | \n
Semagacestat | \nLY450139 | \nEli Lilly & Co. | \nγ-secretase inhibitor | \nDiscontinued in phase 3 | \nNCT01035138 NCT00762411 NCT00594568 | \nLack of clinical improvement Increased risk of skin cancer and infections. | \n
Avagacestat | \nBMS-708163 | \nBristol-Myers Squibb | \nNotch-sparing γ-secretase inhibitor | \nDiscontinued in phase 3 | \nNCT00890890 | \nLack of clinical improvement Increased rate of skin cancers | \n
Begacestat | \nGSI-953 | \nPfizer | \nNotch-sparing γ-secretase inhibitor | \nPhase-1 trial completed | \nNCT00547560 | \n– | \n
Tarenflurbil | \nR-flurbiprofe MPC-7869 | \nMyriad Genetics & Laboratories | \nγ-Secretase modulator | \nDiscontinued in phase 3 | \nNCT00105547 NCT00380276 NCT00322036 | \nLack of clinical improvement Low potency and poor brain penetration | \n
Tramiprosate | \nNC-531 Homotaurine 3APS | \nNeurochem, Inc | \nAβ aggregation inhibitor | \nDiscontinued in phase 3 | \nNCT00314912 NCT00088673 NCT00217763 | \nLack of clinical improvement | \n
Scyllo-inositol | \nAZD-103 ELND005 | \nElan Corporation, Speranza Therapeutics, Transition Therapeutics, Inc. | \nAβ aggregation inhibitor | \nDiscontinued in phase 2 | \nNCT00568776 NCT00934050 | \nLack of clinical improvement | \n
Rosiglitazone | \nAvandia | \nGlaxoSmithKline | \nAnti-diabetic drug Aβ clearance enhancer | \nDiscontinued in phase 3 | \nNCT00428090 NCT00550420 | \nLack of clinical improvement | \n
AN-1792 | \nAIP 001 | \nJanssen Pfizer | \nAβ-targeted active immunotherapy | \nDiscontinued in phase 2 | \nNCT00021723 | \nBrain inflammation Aseptic meningoencephalitis | \n
Bapineuzumab | \nAAB-001 | \nJanssen Pfizer | \nAβ-targeted passive immunotherapy | \nDiscontinued in phase 3 | \nNCT00676143 NCT00667810 NCT00998764 NCT00996918 | \nLack of clinical improvement | \n
Solanezumab | \nLY2062430 | \nEli Lilly & Co. | \nAβ-targeted passive immunotherapy | \nOngoing in phase 3 | \nNCT00905372 NCT00904683 NCT01127633 NCT01900665 | \n– | \n
Gantenerumab | \nRO4909832 RG1450 | \nChugai Pharmaceutical Co. Ltd. Hoffmann-La Roche | \nAβ-targeted passive immunotherapy | \nOngoing in phase 3 | \nNCT01224106 NCT02051608 | \n– | \n
Aducanumab | \nBIIB037 | \nBiogen | \nAβ-targeted passive immunotherapy | \nOngoing in phase 3 | \nNCT02477800 NCT02484547 | \n– | \n
Ponezumab | \nPF-04360365 | \nPfizer | \nAβ-targeted passive immunotherapy | \nDiscontinued in phase 2 | \nNCT00722046 NCT00945672 | \nLack of clinical improvement | \n
Valproate | \nDepakote, Depakene | \nAbbott Laboratories | \nTau phosphorylation inhibitor | \nDiscontinued in phase 3 | \nNCT00071721 | \nLack of clinical improvement Brain volume loss | \n
Lithium ** | \nLithium carbonate | \nPublic institutions | \nTau phosphorylation inhibitor | \nOngoing in phase 2 | \nISRCTN72046462 (see at isrctn.com) NCT01055392 NCT02129348 NCT00088387 | \nDiscrepant results reported Apparently effective in early AD (amnestic MCI) but not in mild-to-moderate AD | \n
Epothilone D | \nBMS-241027 | \nBristol-Myers Squibb | \nMicrotubule stabilizer | \nDiscontinued in phase 1 | \nNCT01492374 | \nNo reasons reported regarding discontinuation in phase 1 | \n
TPI 287 | \n– | \nCortice Biosciences | \nMicrotubule stabilizer | \nOngoing in phase 1 | \nNCT01966666 | \n\n |
Methylthioninium (MT) | \nMethylene Blue Rember TM TRx-0014 | \nTauRx Therapeutics Ltd | \nTau aggregation inhibitor | \nDiscontinued in phase 2 | \nNCT00684944 NCT00515333 | \nDiscrepant results reported Blinding of phase-2 trial has been questioned | \n
LMT-X | \nMethylene Blue TRx-0237 | \nTauRx Therapeutics Ltd | \nTau aggregation inhibitor | \nPhase 3 completed | \nNCT01689233 NCT01689246 NCT01626378 | \nNo results available as yet | \n
ACI-35 | \n– | \nAC Immune SA Janssen | \nTau-targeted active immunotherapy | \nPhase 1 completed | \nISRCTN13033912 (see at isrctn.com) | \n– | \n
AADvac1 | \nAxon peptide 108 conjugated to KLH | \nAxon Neuroscience SE | \nTau-targeted active immunotherapy | \nOngoing phase 1 | \nNCT02031198 | \n– | \n
RG7345 | \nRO6926496 | \nRoche | \nTau-targeted passive immunotherapy | \nDiscontinued in phase 1 | \nNCT02281786 | \nNo reasons reported regarding discontinuation in phase 1 | \n
Developed disease-modifying drugs for AD treatment in clinical trials.
Clinical mutations in PS1 are supposed to induce a loss of γ-secretase function that in turn prevents Aβ generation and increases the Aβ 42/40 ratio (an increase in the longer vs. shorter Aβ isoforms) [31]. Such loss of function is then translated into increased neuronal Aβ production, which is further potentiated with the ageing in AD mice harboring FAD mutations [23, 58]. This pathological mechanism is associated with accumulation of autophagic vesicles in axonal dystrophies surrounding amyloid plaques, which are principally formed by long hydrophobic isoforms of Aβ like Aβ42. Therefore, γ-secretase inhibition or modulation has also been studied as a plausible therapeutic approach against AD, although non-specific effects hinder the development of γ-secretase inhibitors (GSI) as DMDs given that γ-secretase also cleaves several type-I transmembrane proteins such as the Notch receptor, N-cadherin, ErbB4, and p75NTR (see Section 2).
\nSemagacestat was the first GSI to undergo clinical trials, and it reduced Aβ concentrations in the mouse CNS and human plasma [107, 108]. Two large phase-3 trials with semagacestat were prematurely interrupted due to serious adverse events, including hematological alterations, and an increased risk of skin cancer and infections that were attributed to inhibition of the Notch signaling pathway. Furthermore, a worsening of cognition was observed in AD-treated patients [109]. Notch-sparing GSIs (second generation inhibitors) and modulators (agents that shift γ-secretase cleavage from longer to shorter Aβ species without affecting Notch cleavage) were then designed for clinical development. Avagacestat and begacestat were first conceived as notch-sparing GSIs that supposedly display greater selectivity for APP than for Notch cleavage [10], although this was recently reported not to be the case [31]. Therefore, these drugs are also likely to fail and indeed, the poor clinical efficacy of Avagacestat was coupled to an increased rate of skin cancers, again suggesting side effects attributable to Notch signaling inhibition (see Table 1). Finally, some non-steroidal anti-inflammatory drugs (NSAIDs) modulate γ-secretase (GSMs), decreasing the abundance of Aβ42 while increasing that of Aβ38. Tarenflurbil (the R-enantiomer of flurbiprofen) was tested in a phase-3 trial but it did not slow cognitive decline in patients, while it did increase the frequency of dizziness, anemia, and infection. This failure of tarenflurbil was attributed to its low potency and poor brain penetration [10, 99].
\nAggregation of Aβ monomers into higher molecular weight oligomers is thought to be a key neurotoxic event leading to neurodegeneration in the amyloid pathology [7]. For this reason, some DMDs also target this conversion to fight AD. Tramiprosate and scyllo-inositol are two compounds that prevent the transition from Aβ monomers to oligomers, thus favoring Aβ clearance from the brain by insulin-degrading enzyme (IDE) and neprilysin [110]. In addition, scyllo-inositol can also directly bind to Aβ oligomers, promoting their dissociation. Both these drugs have been involved in phase-2 clinical trials and both reduced Aβ42 levels in the CSF of treated patients. In a larger phase-3 study, tramiprosate failed to induce clinical improvement, and thus, further clinical evaluation is still necessary. Scyllo-inositol, also failed to produce significant clinical improvement in a phase-2 trial. Rosiglitazone is an anti-diabetic drug that improves spatial learning and memory abilities, and it mildly decreases Aβ42 brain levels by activating PPARγ and upregulating IDE in AD mice [111]. This drug was involved in phase-2 and phase-3 clinical trials, although the inconclusive results in phase 2 were followed by a lack of clinical efficacy in a larger phase-3 study [99, 112].
\nAnother therapeutic approach to promote Aβ clearance was based on immunization toward Aβ. Active immunization by vaccination stimulates the immune response to promote antibody formation against pathogenic forms of Aβ, such as Aβ42. Active Aβ immunotherapy has been studied since 1999 when the generation of Aβ antibodies was shown to produce clearance of cerebral Aβ by phagocytic microglia in animal models [113]. Unfortunately, this revolutionary approach soon suffered its first setback in a phase-2 trial to test active immunization using full length human Aβ42 peptide, with some patients developing brain inflammation with aseptic meningoencephalitis and provoking the termination of the clinical study [99]. Passive immunotherapy is an alternative strategy and recent approaches were based on shorter Aβ immunogens, such as the humanized monoclonal antibody to Aβ1–5, bapineuzumab, which binds to both soluble and fibrillar forms of Aβ. Despite the evidence of adverse effects in phase-1 trials, bapineuzumab advanced to phases 2 and 3 where it failed to demonstrate clinical efficacy in patients with AD. Another antibody against Aβ is Solanezumab, a humanized monoclonal antibody against Aβ16–24 that preferentially binds to soluble Aβ. In phase-2 trials, solanezumab was found to be safe while increasing plasma and CSF levels of Aβ40 and Aβ42, an indication of decreased plaque load in the brain. However, solanezumab had no effect on behavioral outcomes. Despite the lack of efficacy in phase 2, the antibody advanced to phase-3 trials in patients with mild-to-moderate AD where the primary endpoints, both cognitive and functional, were not achieved [18]. Many other humanized antibodies have been developed, directed at different regions of the Aβ peptide, some entering phase-3 trials (Gantenerumab and Aducanumab) and others having been discontinued (Ponezumab; Table 1).
\nAccording to the amyloid cascade hypothesis, Aβ accumulation precedes and drives tau hyperphosphorylation via the activation of different kinases, including cyclin dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β) [14, 114]. Tau hyperphosphorylation is thought to destabilizes neuronal microtubules, impairing axonal transport and leading to neurite pathology, finally resulting in deficient synaptic function and neuronal death [115, 116] (see Section 2). In this context, DMDs were developed to inhibit tau phosphorylation, as well as compounds that prevent tau aggregation. GSK3β is the main enzyme involved in tau hyperphosphorylation, and lithium and valproate are both drugs that inhibit GSK3β and reduce tau phosphorylation in animal models [117]. Unexpectedly, valproate impaired the cognitive and functional status, and it was also associated with a reduced brain volume in patients with AD receiving the drug in clinical trials [118]. Lithium is neuroprotective in animal models of AD, not only via the inhibition of GSK-3β but also through the remodeling of Aβ plaques, leading to a decrease in the number of dystrophic axons, reduced neuronal degeneration and improved cognitive scores in AD mice [119, 120]. However, no conclusions have been reached regarding the clinical efficacy of lithium for AD treatment. Some clinical trials failed to demonstrate a protective effect of lithium on cognitive performance, although a more recent clinical study showed that lithium reduced cognitive decline patients with early AD (amnesic MCI) [121, 122]. Tau hyperphosphorylation compromises its ability to bind to microtubules in AD, provoking microtubule instability. In this sense, epothilone D and TPI 287, synthetic paclitaxel-derived microtubule-stabilizing drugs with good BBB permeability, were assessed in phase-1 trials of safety and tolerability. Unfortunately, epothilone D was recently discontinued (see Table 1). Tau hyperphosphorylation also provokes tau aggregation which is also considered a key neurotoxic event in AD [123]. LMT-X is a new version of methylene blue, a compound that was tested and discontinued in a phase-2 trial to treat AD. LMT-X is an inhibitor of tau aggregation that specifically disrupts tau-tau interactions in the microtubule binding region. In a phase-2 trial, this new drug slowed down the cognitive decline in a subgroup of patients, and it is now being tested in phase-3 trials, although information about clinical efficacy is not yet available [124, 125]. Finally, two tau-derived peptide vaccines that stimulate active immunization entered phase I studies: AADvac1 and ACI-35. AADvac1 is a synthetic peptide corresponding to a naturally occurring, truncated and misfolded form of tau. ACI-35 is a liposomal vaccine containing a synthetic peptide corresponding to human protein tau sequence 393–408 (numbering according to the tau 2N4R isoform), with phosphorylated S396 and S404 residues. Vaccination with these peptides improves neurobehavioral deficits in AD rodents while ACI-35 is characterized by a rapid and robust polyclonal antibody response specific to phosphorylated tau in WT and AD mice [125]. In addition, passive immunization has also been investigated using a humanized monoclonal antibody targeting pS422 phospho-tau. In AD mice, chronic administration of this antibody reduced hyperphosphorylated tau accumulation [126], although clinical studies with this antibody were recently discontinued in phase 1 (see Table 1).
\nThe aforementioned therapeutic approaches summarize the attempts to develop DMDs based on the amyloid cascade hypothesis, principally focused on Aβ and hyperphosphorylated tau protein. With several anti-amyloid drugs now having failed in late stage clinical trials, many critical voices in the scientific community have questioned the validity of the amyloid hypothesis to explain the pathophysiology of AD and as platform on which to develop DMDs for AD therapy. Moreover, the incidence of serious side effects observed in human trials is another drawback to the clinical development of these types of drugs, particularly when many of these adverse effects are associated with the mechanism of action of the compounds tested. However, the amyloid hypothesis cannot be disregarded due the lack of reliable biomarkers to detect efficacy at early stages, and because many of the compounds in clinical trials cross the BBB poorly or cause side effects that forced trials to be discontinued before efficacy could be evaluated [18, 127].
\nOver the last 2 decades, the relationship between cholesterol levels and the risk of developing AD has become more evident, in turn encouraging the use of statins to treat or prevent AD (see Section 3.1.). Statins are a group of drugs used to treat hypercholesterolemia as they inhibit HMG-CoA reductase, the principal enzyme involved in cholesterol synthesis. In animal models of AD, simvastatin administration to guinea pigs decreased brain and CSF Aβ levels, an effect that is reversed by discontinuing the treatment [128]. By contrast, simvastatin failed to modify brain levels of Aβ in other studies but it improved the cognitive capacity of transgenic AD mice [129]. Thus, it appears that simvastatin can possibly prevent cognitive decline in AD mice without affecting amyloidogenic APP processing, in turn suggesting that the amyloid pathology may be a consequence more than the primary causal agent of AD, possibly due to changes in membrane lipids. In another study, lovastatin and pravastatin reduced the amount of Aβ in the brains of AD mice, while simultaneously increasing the levels of sAPPα [130]. Therefore, the results of preclinical research into these drugs are encouraging, although the outcome of human studies has been inconsistent, in part due to the differences in study design and data analysis [131].
\nWhile several observational studies in human subjects support the hypothesis that statins may prevent AD development, other studies argue against such effects [132]. Nevertheless, some clinical trials are investigating the use of statins in AD, such as simvastatin or atorvastatin. The first trial to analyze the effect of simvastatin on cognitive scores and APP processing was completed in 2003. This clinical study was performed over 12 weeks on patients with AD, and it reported changes in APP metabolites in the CSF: sAPPα and sAPPβ levels were significantly reduced but not those of Aβ or tau. Remarkably, a significant cognitive improvement in response to simvastatin treatment was found in patients with AD [133]. Unexpectedly, subsequent results based on a 12 month treatment failed to show such cognitive improvements in the same patients, even though cholesterol metabolism was altered in the brain [134]. Unfortunately, a later larger trial performed on 406 mild-to-moderate AD patients also failed to identify clinical benefits of simvastatin (the multicenter CLASP trial). This CLASP trial (clinicaltrials.gov ID: #NCT00053599) evaluated the safety and efficacy of an 18 month treatment with simvastatin to prevent AD progression. Once again, simvastatin treatment lowered lipid levels but it did not slow the progressive AD-related decline in cognitive performance [135]. Despite the apparent lack of clinical improvement on cognition in patients with AD, the University of Wisconsin (Madison, USA) evaluated simvastatin in cognitively normal people at risk of developing FAD. This study (ESPRIT study: clinicaltrials.gov ID: #NCT00486044), compared the changes in CSF Aβ and cognitive scores following simvastatin or placebo administration, as well as markers of cholesterol metabolism and inflammation. Again, no specific effect of simvastatin was observed on CSF Aβ or tau levels but a improvement in terms of cognitive performance was reported [136]. As a result, a follow-up study attempted to evaluate similar outcome measures after a longer course of simvastatin (the SHARP study; clinicaltrials.gov ID: #NCT00939822). Additional clinical trials with a more precise methodological design are also being developed to define the clinical efficacy of simvastatin. For instance, the SIMaMCI study (clinicaltrials.gov ID: #NCT00842920) on 445 subjects assesses the time until participants suffer phenoconversion to dementia, with conversion being defined as an increase in the Clinical Dementia Rating (CDR) score above 0.5. The trial also focuses on the change in cognitive scores from a healthy state to MCI and dementia.
\nOther clinical studies have assessed atorvastatin, lovastatin, and pravastatin in AD. The only clinical trial showing cognitive improvement associated with atorvastatin administration was a phase-2 pilot study comparing a 1-year course of atorvastatin to a placebo in patients with mild-to-moderate-AD who were also taking a cholinesterase inhibitor and vitamin E (clinicaltrials.gov: #NCT00024531). This study reported trends towards benefits on cognition and function [137, 138], leading to a larger phase-3 randomized trial involving 640 patients to confirm the potential clinical benefits of atorvastatin in patients with mild-to-moderate AD also treated with donepezil (the LEADe study; clinicaltrial.gov ID: #NCT00151502). Unfortunately, no clinical benefit was observed after 18 months of treatment [139, 140], and this was considered the definitive trial on atorvastatin regarding symptomatic AD treatment. It is worth noting that APP metabolites were not assessed in these studies and that decreased circulating cholesterol, as well as improved neurovascular response and cerebral blood flow were found in atorvastatin-treated patients with AD (clinicaltrials.gov: #NCT00751907) [141]. Lovastatin has been less frequently studied in randomized AD trials, and it was shown to be efficient in reducing serum Aβ levels in patients AD, although no cognitive evaluations were performed (clinicaltrial.gov: #NCT00046358) [142]. In the case of pravastatin, APP processing was not analyzed and the cognitive evaluation of treated patients revealed no significant improvement relative to the placebo group (clinicaltrial.gov: # NCT00303277) [143].
\nThe substantial variability in outcome from these human studies makes it difficult to ascertain whether statins might have a beneficial role in preventing or treating AD. One possible reason to explain such inconsistency relates to the ability of statins to cross the BBB and enter the brain. In this respect, the chemical structure of statins can vary greatly, which justifies why some of them cross the BBB better than others. Accordingly, simvastatin and lovastatin appear to cross the BBB via passive diffusion, whereas pravastatin depends on an active transport system. Although this could justify the lack of clinical effect of pravastatin in clinical trials, it is also true that pravastatin reduced Aβ load in AD mice, suggesting that pravastatin does reach the brain and exert its pharmacological effects [130, 144]. In this sense, clinical studies have investigated different statins with substantial variation in BBB permeability, making it difficult to reconcile the conflicting findings in the literature.
\nAnother confounding factor would be the AD patient’s ApoE genotype which may affect the effectiveness of statins in AD prevention and treatment. In fact, individuals with the ApoE4 allele may experience less benefit from statin treatment in terms of cholesterol levels than others with the E2 or E3 alleles [145]. Therefore, although some trials in humans have taken the ApoE genotype into account, not all do. In addition, statins have a number of pleitropic effects on physiology and metabolism besides lowering cholesterol levels. For instance, statins can alter the expression of genes related to cell growth, signaling, trafficking, and apoptosis, which in turn can potentially affect the results of trials. In this sense, inhibition of HMG-CoA reductase activity can lead to decreased isoprenylation of proteins which in turn may cause a variety of downstream effects [146]. Thus, low isoprenoid levels may inhibit the secretory APP pathway leading to intracellular accumulation of APP metabolites that bias their analysis in the CSF or plasma [147].
\nIn summary, cholesterol-lowering drugs such as statins have potential therapeutic effects for the treatment of AD. Based on preclinical studies in animal models and clinical trials in humans, statins represent a valuable group of compounds with promising therapeutic effects in AD. However, individual statins show different outcomes in terms of APP metabolism and cognitive improvement. In part, these disparities may be explained by the variability in BBB permeability and the different biochemical effects of these drugs observed to date.
\nNeuroprotective effects of long-chain ω-3 PUFAs (see Section 3.2.) encouraged a number of clinical trials to assess the effects of ω-3 fatty acid administration to patients with AD over a defined time period, particularly focusing on the cognitive benefits of DHA and EPA. Interestingly, decreases in plasma DHA are associated with cognitive decline in healthy elderly adults and DHA administration to these patients improved the physiological memory loss and cognitive decline that frequently appears in the elderly [148] (clinicaltrials.gov ID: #NCT0027813). However, DHA administration to patients with AD did not significantly improve cognitive scores [80] (clinicaltrials.gov ID: #NCT00440050). Another randomized study involving administration of a commercially available fish oil as source of DHA and EPA only improved cognition in a small subgroup of patients with very mild cognitive dysfunction, with no clear beneficial effects in most patients [149] (clinicaltrials.gov ID: #NCT00211159). Finally, the most recent trial was carried out on a small group of patients with mild-to-moderate AD who were administered fish oil containing DHA and EPA. In this pilot study, significant recovery of cognitive capacity was evident in the patients treated with fish oil (with or without lipoic acid supplementation) [150] (clinicaltrials.gov ID: #NCT00090402). Together, these studies indicate that DHA supplementation may represent a plausible therapeutic approach for the treatment of the physiological age-related cognitive decline, although it is unclear what type of ω-3 PUFAs could be used to treat AD. Some of these discrepancies in the different randomized studies may reflect the source of the ω-3 PUFAs administered to the patients. As yet there is no consensus with regards the defined sources of ω-3 PUFAs or a standard ratio or dose of DHA and EPA: Quinn et al. [80] evaluated 2 g/day DHA, Freund-Levi et al. [149] evaluated the effect of fish oil administration with a DHA and EPA content of 1.7 and 0.6 g/day, respectively (EPAX 1500 TG; Pronova Biocare, Norway), and Shinto et al. [150] evaluated a fish oil daily dose containing 675 mg DHA and 975 mg EPA, the latter trial being the only efficacious treatment against AD in humans and having a different DHA:EPA ratio with respect to the former.
\nIt is likely that differences in the source of ω-3 PUFAs together with variable DHA:EPA ratios might explain the variation in the results observed when treating AD patients with long-chain ω-3 PUFAs. Moreover, the presence of mercury in some fish oil supplements may provoke some neurological problems that could counteract the beneficial effects of DHA and related compounds. In this context, ω-3 PUFAs also exert their physiological function through the production of hydroxylated bioactive derivatives, such as NPD1 (see Section 3.2.). In fact, it has been demonstrated that NPD1 levels are dramatically reduced in the AD brain, even more so than DHA [68]. These data suggest that abnormally low levels of DHA in AD would be accompanied by impaired conversion of this fatty acid into NPD1 and other RVs. In fact, reduced levels of 15-LOX, the key enzyme involved in the generation of the D-series RVs and protectins, were observed in the brain of patients with AD, in turn demonstrating that lipid second messenger generation from DHA is impaired in AD [68]. Assuming that the conversion of DHA into hydroxylated derivatives is needed to mediate DHA-related physiological activity, such 15-LOX modifications could at least partially explain why DHA administration did not improve cognition in patients with AD. In this context, it is noteworthy that some cognitive improvement was observed when fish oil alone was used as the source of ω-3 PUFAs, suggesting that these oils might contain other PUFAs that impart neuroprotection independently of DHA and EPA (hydroxylated PUFAs such as RVs or other PUFA derivatives) [81]. This hypothesis is supported by the high efficacy of HDHA(see below DHALifort) on cognitive score and by the aforementioned epidemiological meta-analysis showing an inverse correlation between AD incidence and fish oil intake but not with DHA/EPA (ω-3 PUFA) intake (see Section 3.2) [78].
\nDHA-derived NPD1 produces many beneficial effects in animal and cell models of AD [75]. On the one hand, NPD1 suppresses Aβ42 peptide shedding by downregulating BACE-1 activity while enhancing α-secretase activity, thereby upregulating sAPPα levels and shifting the cleavage of APP from the amyloidogenic to the non-amyloidogenic pathway. Thus, NPD1 stimulated secretion of sAPPα strengthens neurotrophic signaling and prevents Aβ oligomer neurotoxicity, which may in turn be accompanied by a number of beneficial effects, such as the prevention of neuronal and axonal injury, improved neuronal plasticity, and enhanced learning memory [151–153]. In addition, like other RVs, NPD1 also displays anti-inflammatory properties. Indeed, NPD1 administration decreases Aβ42-triggered expression of the pro-inflammatory COX-2 and of B-94 (a TNF-α-inducible pro-inflammatory factor), and it prevents apoptosis in cultured cells by upregulating the expression of anti-apoptotic members of the Bcl-2 protein family.
\nThe neuroprotective properties of NPD1 have encouraged the development of new pharmacological approaches based on hydroxylated derivatives of ω-3 PUFAs to treat AD. Regardless of the use of natural RVs and protectins to treat inflammatory and neurodegenerative diseases [154], synthetic ω-3-PUFA bioactive hydroxyl derivatives have also been used to treat such disorders. This kind of therapeutic approach, aimed at modulating brain lipids to treat neurological diseases, is framed within so-called membrane lipid therapy (MLT) [155–157]. In this context, a novel hydroxylated derivative named HDHA (2-hydroxy-docosahexanoic acid) has been proposed as a promising therapeutic approach to treat AD. HDHA (DHALifort; PharmaConcept, Hungary) administration influences the brain lipid composition, increasing the PE species carrying long-chain PUFAs, which are significantly reduced in patients with AD (see Section 3.3.). Upon normalization of the membrane lipid composition by HDHA treatment, the membrane structure recovers the presence of liquid-disordered prone membrane structures [158] (Figure 4). These lipid changes are paralleled with a reduction in Aβ accumulation and tau hyperphosphorylation, and recovery of cognitive scores in a transgenic mouse model of AD (5xFAD mice) [159, 160] (see Figure 4).
\n\nHDHA also enhances the survival of neuron-like cells exposed to different insults, such as oligomeric Aβ and NMDA-mediated neurotoxicity (in vitro), and it promotes hippocampal neuronal cell proliferation in 5XFAD mice in vivo [159, 160], suggesting that HDHA induced neuroregeneration both in vivo and in vitro, which in part may explain its efficacy against neurodegeneration and memory loss. As part of its mechanism of action, HDHA dampens the binding affinity of oligomeric and fibrillar Aβ to lipid-raft membrane domains. Moreover, it enhances the unfolded protein response (UPR) and autophagy in neuron-like cells, which in turn may promote neuronal survival [160, 161]. In this sense, although the molecular role of autophagy in AD is complex and still largely unknown, it is thought that activation of salvage autophagy would avoid the intracellular accumulation of Aβ and its precursors by reducing the neuritic pathology (see Figure 2) [162, 163]. Therefore, the pleitropic effects of HDHA have proven beneficial to treat AD, suggesting that its molecular target is an upstream entity such as the membrane lipid bilayer. Thus, the normalization of the PE, DHA, cholesterol, and SM content mediated by HDHA would restore membrane lipid structure, which in turn would regulate amyloidogenic secretase activity tau phosphorylation and neuronal degeneration.
\nProof of concept for the use of HDHA in AD mice and the proposed molecular mechanism of action. (A) Diagrams showing representative outlines of control and AD mice (5xFAD mice) that received HDHA or the vehicle alone, in the Radial Arm Maze test (RAM). A black point at the end of one arm represents where the mice find a food pellet. (B) Quantitative analysis of test performance is addressed by quantifying working (reentry of an arm already visited) and reference (entry into an unbaited arm) memory errors. Both parameters increased significantly in AD mice while HDHA treatment prevented such behavioral impairment until cognitive scores were almost totally reverted to those of the controls. Bars represent the mean ± SEM. One-way ANOVA followed by Bonferroni’s post hoc test: *p < 0.05, difference relative to healthy controls; #: p < 0.05 difference relative to the untreated AD group. C) Postulated mechanism of action for HDHA. HDHA enriches brain membranes in PE carrying DHA and other long PUFAs. These lipid changes may influence the structure of the cell membrane by promoting the appearance of liquid-disordered prone structures and potentially preventing AD-related cell signaling by: (i) downregulating APP amyloidogenic processing and Aβ-induced tau protein hyperphosphorylation; and (ii) decreasing neuron vulnerability to extracellular toxic agents such as oligomeric Aβ. Together, this evidence supports a neuroprotective role of HDHA that may be associated with the improved cognitive capabilities observed in AD mice. Adapted from [159, 160].
Interestingly, the cellular heat shock response (HSP) depends on the plasma membrane composition, such that increased membrane fluidity is related to enhanced expression of heat-shock proteins (HSP) [164]. In this context, these proteins (particularly Hsp70, Hsp60, and Hsp27) are involved in the mechanism of action of lithium in compacting Aβ plaques, lowering the density of dystrophic neurites and preventing neuronal degeneration in a mouse model of AD [119]. Therefore, lipid derivatives like HDHA that enhance membrane fluidity might also reduce the neurite pathology and prevent neuronal loss in AD via a mechanism involving Hsp expression. Regardless of amyloid production and the neuritic pathology, inflammation is also a key player in AD. In this sense, another synthetic hydroxyl derivative of ARA, 2-HARA (2-hydroxy-arachidonic acid) is a COX-1 and COX-2 inhibitor [165]. The inhibitory effect over COX-1 has been related to alternative microglia activation, as well as reduced Aβ production and tau hyperphosphorylation in a transgenic model of AD [166]. Thus, 2-HARA may be a promising therapeutic approach to mitigate the inflammatory component of AD, driving microglia activation towards an alternative neuroprotective phenotype, and reducing AD-related amyloid and tau pathologies. To summarize, MLT is a therapeutic concept targeting membrane lipids that could be used to treat neurological disorders such as AD. In this context, recent findings about ω-3 PUFA RV-like mediators, such as HDHA and 2-HARA, offer a wide range of possibilities to design new bioactive compounds to treat neurodegenerative diseases.
\n\n\nAfter adipose tissue, the human brain is the organ with the largest amount of lipids in the body. There is compelling evidence that lipid homeostasis is altered in AD, suggesting that the plasma membrane lipid composition and structure plays a critical role in the pathophysiology of AD and hence in its therapy. Therefore, lipid alterations might be responsible for other downstream neuropathological hallmarks of AD, including amyloid and neurite pathologies, as well as inflammation and neuron loss, which eventually causes the cognitive deterioration evident in patients with AD. Accordingly, a number of clinical trials have been set up to investigate how the regulation of cholesterol and PUFA hydroxyl derivatives such as HDHA may constitute promising therapeutic approaches to treat this devastating condition.
\nThe PubMed database (NCBI, National Library of Medicine, USA) was searched for relevant, both original and review, articles using the keywords mentioned at the beginning of the present chapter either by separate or with multiple combinations. The papers were selected accordingly to their adhesion to the main subject of the present review and the expert authors’ knowledge of the field. In addition, interesting and useful information has been achieved from http://www.alzforum.org/ and http://clinicaltrials.gov/, as well as from books at the Library of the University of the Balearic Islands (Palma de Mallorca, Spain).
\nSpringer is the original publisher of images shown in Figure 2. These pictures were reproduced with permission from Springer and were adapted from [12] (please see full credits in the reference list). The authors wish to thank the original publisher as well as the original authors (Dr. Isidre Ferrer and co-workers) for allowing reproduction of these images in the present work. Information concerning clinical trials of several drugs has been obtained from the website http://www.alzforum.org/therapeutics. This work was supported in part by grants from the Spanish Ministerio de Economía y Competitividad (BIO2010-21132, IPT-010000-2010-16, BIO2013-49006-C2-1-R, RTC-2015-3542, RTC-2015-4094 to PVE and XB), with co-financing from EU FEDER funds, by grants to Research Groups of Excellence from the Govern de les Illes Balears, Spain (PVE), and by the Marathon Foundation (Spain). MT was a recipient of a Torres-Quevedo contract from the Spanish Ministerio de Economía y Competitividad.
\nWe are living in a world of many challenges such as climate changes, polluted environment, resource depletion, and increasing demand for fuel. The use of oil reserves to fulfill our need of fuel has caused many drastic challenges from energy security to change in temperature. Rapid industrialization has increased the demand of petroleum products and consequently has raised the monopoly of few countries, which can manipulate petroleum price and create instability. This may also create environmental problems by emission of greenhouse gases and subsequently effect on climate change. The most important source of energy is petroleum that is largely used in transportation and industries; therefore, viability of liquid fuel is enhanced. As the environmental issues are growing, more research is being conducted to address the problems. The search for alternative source of petrol that is less costly with minimal environmental effects has become the center of attention. For instance, biomass is considered as a sustainable resource that can be utilized in large-scale production of biofuel that can be utilized as an alternative source of fuel and may present solution to environmental problems. Furthermore, relying on fossil fuel could be detrimental as it has been predicted of its depletion by 2050. The total annual primary production of biomass is over 100 billion tonnes of carbon per year, and the energy reserve per metric tonne of biomass is between 1.5E3 and 3E3 kW hours that is sufficient to cater the needs of the world energy requirements [1].
\nBioenergy products like bioethanol, biohydrogen, and biodiesel can be obtained from lignocellulose biomass which is considerably large renewable bioresource and obtained from plants. The term “lignocellulosic biomass” is defined as lignin, cellulose, and hemicellulose that constitute the plant cell wall. Strong cross-linking associations are present between these components that cause hindrance in the breakdown of plant cell wall. Polysaccharides and lignin are cross-linked via ester and ether linkages [2, 3, 4]. Microfibrils that are formed by cellulose, hemicellulose, and lignin help in the stability of plant cell wall structure [5, 6].
\nLignocellulose was first produced from food crop such as corn, oilseed, and sugarcane. But the use of edible feedstock for bioenergy products formation is being discouraged to prevent the rise in food competition. Thus, second-generation biofuels are obtained from plants wastes to avoid competition of land and water resources between energy crops and food crops. Currently, lignocellulose is being produced from wood residues, agricultural residues, food industry residue, grasses, domestic wastes, municipal solid wastes, and nonfood seeds [7, 8, 9]. The lignocellulose wastes (LCW) are largest renewable bioresource reservoir on earth that is being wasted as pre and postharvest agricultural wastes. Thus, many steps need to be adopted for use of these renewable resources for the production of bioenergy products. Recovery of many products like enzymes, methane, activated carbon, lipids, resins, methane, carbohydrates, surfactants, resins, organic acids, ethanol, amino acids, degradable plastic composites, biosorbents, biopesticides, and biopromoters can be achieved by utilizing LCW. The added benefits of using LCW besides recovery of different products are the removal of LCW waste from the environment. Also, utilization of LCW eliminates the use of food for bioethanol production. The US government has planned the production of 21 billion gallon of biofuels by 2022 [2, 5]. Biofuel production from lignocellulosic biomass reduces the emission of greenhouse gases.
\nPretreatment brings physical, biological, and chemical changes to biomass structure; therefore, it is very important to consider the type of pretreatment. In order to break down the hindrance caused by strong association within the cell wall, pretreatment is an important step which can increase the availability of lignocellulosic biomass for cellulase enzymes, their digestibility, and product yield. Before subjection to enzymatic hydrolysis, pretreatment of biomass can increase the rate of hydrolysis by 3–10-fold. Pretreatment of LCW is not an easy step as it seems after the installation of power generator; pretreatment is the second most costly process at industrial level. In crystalline cellulose, the disruption of hydrogen bonds, cross-linked matrix disruption, and increase in porosity as well as surface area of cellulose are the three tasks that are performed via a suitable pretreatment methods. The outcome of pretreatment also differs due to the difference in the ratio of cell wall components [10, 11]. The option to use dilute acid pretreatment method is more effective against poplar tree bark or corn as compared to the same method used for sweet gum bark or cornstalks. Few requirements of an effective, efficient, and economically suitable pretreatment process that including use of cheap chemicals, very less consumption of chemicals, prevention of hemicellulose and cellulose from denaturation, minimal energy requirement and consumption, cost-effective size reduction process, and reactive cellulosic fiber production are the factors that need to be considered for pretreatment. There are several methods of pretreatment that can be divided into four categories, namely, chemical, physical, biological, and physiochemical pretreatment [12, 13, 14, 15].
\nPore size and surface area of lignocellulosic biomass can be increased, whereas crystallinity and degree of polymerization of cellulose can be decreased with the application of physical methods. Physical pretreatments include milling, sonication, mechanical extrusion, ozonolysis, and pyrolysis.
\nOn the inherent ultrastructure of cellulose and degree of crystallinity, milling can be performed to render lignocelluloses more amenable to cellulases. Cellulases are enzyme that catalyze cellulose, but for the catalysis and best results, the substrate availability needs to be enhanced for optimized functioning of the enzymes. Before the subjection of the LCW to enzymatic hydrolysis, milling and size reduction of the lignocellulosic matter should be performed. Milling process has several types like ball milling, colloid milling, vibro-energy milling, hammer milling, and two-roll milling. For wet material, colloid mill, dissolver, and fibrillator are suitable, whereas for dry materials hammer mill, extruder, cryogenic mill, and roller mill are used. For both wet and dry material, ball milling can be used. For waster paper, hammer milling is the most suitable pretreatment option. Enzymatic degradation can be improved by milling as it reduces the degree of crystallinity and material size. Up to 0.2 mm reduction in particle size can be seen by milling and grinding. Reduction in particle size of biomass can be achieved up to a certain limit; beyond that limit reduction in particle size does not effect in the pretreatment procedure. Corn stover with small particle size, i.e., from 53 to 75 μm, is more productive as compared to large particle size corn stover ranging from 475 to 710 μm. The difference in particle size shows that productivity can significantly affect the pretreatment process. Ball milling causes a massive drop in crystallinity index from 4.9 to 74.2% which makes this process more suitable for saccharification of straw at mild hydrolytic conditions with more production of fermentable sugars [12, 16, 17, 18]. For better results of hydrolysis, milling can be used in combination with enzymatic hydrolysis. Mechanical action, mass transfer, and enzymatic hydrolysis can be achieved at the same time when two methods are combined. A number of ball beads in bill mill reactor play a crucial role in the α-cellulose hydrolysis, as less enzyme loading is required, and 100% rate of hydrolysis can be achieved in comparison to pretreatment of biomass that is carried without the use of milling procedure. Highest hydrolysis rate with high yield of reducing sugar was obtained when rice straw was put into fluidized bed opposed jet mill for fine grinding after cutting, steam explosion, and pulverization. For pretreatment of biomass, ball milling is an expensive option in terms of energy consumption, which is a huge disadvantage at industrial scale. Also, incapability of milling for removing lignin makes it a less suitable option as enzyme accessibility to the substrate is reduced in the presence of lignin. Reduction in crystallinity, degree of polymerization, and increase in surface area can be effected by the type of biomass, type of milling used for pretreatment, and duration of the milling process [19, 20, 21].
\nFor improving digestibility and reducing crystallinity, vibratory ball milling is very effective. Low energy consumption has an important advantage of using wet disk milling which produces fibers that improve hydrolysis of cellulose, whereas hammer milling produces finer bundles. Due to this reason milling is not preferred when wet disk milling is available [22, 23]. Other study results of conventional ball and disk milling are compared. With the use of conventional ball milling, maximum yields of xylose and glucose were obtained, i.e., 54.3 and 89.4%, respectively [24]. Wet milling produces less yield, but it has the advantage of not producing inhibitors and very low energy consuming capability. An increase of 110% in enzymatic hydrolysis was achieved when wet milling was combined with alkaline pretreatment. Optimum parameters for wet milling pretreatment of corn stover were 10 mm diameter 20 steel balls, 1:10 solid-to-liquid ratio, 350 rpm/min speed, and 0.5 mm particle size [25] (Figures 1 and 2).
\nColloid milling (Pharmapproach.com).
Hammer milling (Solidswiki.com).
Commonly used method for plant biomass pretreatment is microwave irradiation. This pretreatment method has several advantages that include ease of pretreatment, increased heating capacity, short processing time, minimal generation of inhibitors, and less energy requirement. Microwave irradiation in closed container was first reported in 1984 by team of researchers from Kyoto University, Japan. They treated sugarcane bagasse, rice straw, and rice hulls with microwaves in the presence of water. The conditions used for microwave treatment include glass vessels of 50 mL, 2450 MHz energy, and 2.4 kW microwave irradiation [26]. Classical pretreatment methods were carried out at high pressure and temperatures. Chemical interactions between lignocellulosic material break as a result of high temperature, thus increasing substrate availability to the enzymes. Under high-pressure steam injection or indirect heat injection, high temperature between 160 and 250°C is provided to lignocellulosic material in conventional heating methods. However, in order to prevent temperature gradients, crushing of lignocellulosic material into small particles is needed. To avoid large temperature gradients, microwave is a good choice as it uniformly distributes heat which also avoids degradation of lignocellulosic material into humic acid and furfural. For effective degradation, microwave irradiation is combined with mild alkali treatment. Sugar yield of 70–90% from switch grass was obtained from alkali and irradiation combined pretreatment [27]. As microwave irradiation is performed at high temperature, therefore, closed containers are required to achieve high temperature. Three properties, namely, penetration, reflection, and absorbance are exhibited by microwave. Microwave passes through glass and plastic, absorbed by water and biomass, whereas microwaves are reflected by metals. Based on these properties, microwave reactors can be divided into two types, one that allows the passage of microwaves, whereas the other kind reflects the microwaves. Glass or plastic is the building material of the first type of microwave reactors, whereas the second types of reactors are composed of steel. Through quartz windows, microwaves can enter into the reactor as these are placed in the reactor. Closed, sealable, pressure-resistant glass tube container having gasket made up of Teflon can be used for the high temperature, i.e., 200°C, for microwave irradiation pretreatment. Sensors are used to control and ensure temperature inside the microwave. Teflon-coated sensors are a good choice because of the thermostability, corrosion-free nature, and zero absorbance properties. In a microwave oven, Teflon vessels are used by some scientists due to its advantageous properties [28, 29]. Normally vessel sizes vary from 100 mL to several hundred milliliters. A 650 mL vessel with 318 mm length, connected nitrogen bottle, gauges, and thermometers are installed on the top of the microwave that was designed by Chen and Cheng [30]. Besides the glass vessels and stainless steel tanks with temperature and pressure sensors, automatic controlling system for microwave input and mechanical stirrer are also used (Figure 3).
\nMicrowave irradiation (Researchgate.net).
When materials that can pass through a defined cross section die, it appears out with the fixed definite profile. This is the extrusion process which is known for sugar recovery from biomass. Adaptability to modifications, no degradation products, controllable environment, and high throughput are few advantages related to mechanical extrusion pretreatment process. Single screw extruder and twin screw extruder are two types of extruders.
\nSingle screw extruder is based on three screw elements, forward, kneading, and reverse. With the minimum shearing and mixing, bulk material of varying pitches and lengths can be transported by forward screw element. Prominent mixing and shearing effect is produced by kneading screw elements with weak forward conveying effect, whereas the use of immense mixing and shearing involves material that is pushed back by reverse screw elements. A screw configuration is defined by the arrangement of different stagger angels, lengths spacing, pitches, and positions. Twin screw extruder can accomplish multiple tasks at the same time like mixing, shearing, grinding, reaction, drying, and separation. High enzymatic hydrolysis rates are achieved by the use of single and twin screw extruders. Different parameters like speed of screw, temperature of barrel, and compression ratio can significantly affect recovery of sugars. Short-time extruders provide fast heat transfer, proper mixing, and increased shear. When material passed through the extruder barrel, structure of biomass is disturbed, exposing more surface for enzymatic hydrolysis [31, 32, 33]. During extrusion process, lignocellulosic material can be treated with alkali or acid in order to increase sugar recovery. Acidic treatment is less preferred than alkali because of the corrosion caused by acid to the extruder material. Corrosion problem can be solved by the use of AL6XN alloy for barrel fabrication and screws of extruder. With less carbohydrate degradation and role in the delignification, alkali treatment is suitable for lignocellulosic material. Sodium hydroxide is most commonly used to break ester linkages and solubilization of lignins and hemicelluloses. Alkali treatment can be applied by addition of alkali using volumetric pump into the extruder or by soaking the lignocellulosic material in alkali at room temperature [31, 34, 35] (Figure 4).
\nTwin screw extruder (Researchgate.net).
For the production of bio oil from biomass, process of pyrolysis is used. Pyrolysis is a thermal degradation of lignocellulosic biomass at very high temperature without the presence of oxidizing agent. At temperature ranging between 500 and 800°C, pyrolysis was performed. Rapid decomposition of cellulose resulted in the formation of products like pyrolysis oil and charcoal [36]. Based on temperature, pyrolysis pretreatment process is divided into fast and low pyrolysis. Certain factors affect the end products like biomass characteristics, reaction parameters, and type of pyrolysis. Due to high-value energy-rich product formation, easy transport management retrofitting, combustion, storage, and flexibility in utilization and marketing, thermal industries are adapting to the process of pyrolysis. Presence of oxygen and less temperature increase the efficiency of this process. A study on the bond cleavage rate of cellulose was carried out in the presence of nitrogen and oxygen. During the process of pyrolysis, breakage of 7.8 × 109 bonds/min/g cellulose in the presence of oxygen and breakdown of 1.7 × 108 bonds/min/g cellulose in the presence of nitrogen at 25°C were observed. In order to obtain more efficiency and results, microwave-assisted pyrolysis is preferred due to the microwave dielectric heating [37]. Thermochemical conversion of biomass into biofuels can be performed via three technologies, gasification, pyrolysis, and direct combustion [38]. Different yields of products from pyrolysis are due to different modes of pyrolysis. Bio oil is a mixture of polar organics and water. Pyrolysis is used where bio oil production is required. Fast pyrolysis in a controlled environment leads to the formation of liquid products (fuels). Torrefaction is an emerging technique which is also known as mild pyrolysis. It differs from pyrolysis with reference to thermochemical process that is carried out at temperature range between 200 and 300°C. Partial decomposition of biomass occurs in this process, and ultimate product obtained is terrified biomass. Whereas, in the process of pyrolysis, plant biomass is decomposed into vapor, aerosols, and char. Torrefaction has been categorized into two categories based on dry and wet torrefaction.
\nDry torrefaction needs an inert environment and completely dry biomass and normal atmospheric pressure. Biochar is the major product in this type of biomass pretreatment. Hydrothermal carbonization and hydrothermal torrefaction are other terminologies used for wet torrefaction. Unlike dry torrefaction, pressurized vessel of water is used to carry out the pretreatment. Biomass used for wet torrefaction contains moisture content, but after torrefaction, a drying process is necessary in this type of torrefaction. A pressure between 1 and 250 MPa is required to carry out wet torrefaction. Biomass used during wet torrefaction pretreatment produces hydro-char as a main product [39].
\nIn this method, pores are created in the cell membrane due to which cellulose exposes to such agents that cause its breakdown by entering into the cell. High voltage ranging between 5.0 and 20.0 kV/cm is applied in a sudden burst to biomass for nano- to milliseconds. Sample was placed between two parallel plate electrodes, and the strength of electric field is given as E = V/d, where V and d are voltage and distance, respectively, between plate electrodes. Dramatic increase in mass permeability and tissue rapture occurred on the application of electric field. Electric pulses are applied, generally in the form of square waves or exponential decay. Setup of pulse electric field consisted of pulse generator, control system, data acquisition system, and material handling equipment [40, 41]. At ambient temperatures, the treatment can be performed at low energy. Another advantage of this treatment is the simple design of the instrument. Short duration of pulse time saves the effort and energy [42, 43]. Pulse electric field pretreatment was applied to pig manure and waste activated sludge by Author et al. [44]. As compared to untreated manure and sludge, 80% methane from manure and twofold increase in methane production from sludge were recorded in the study. A PEF system was designed and developed by Kumar et al. [45] that consisted of high-voltage power supply, switch circuit, a function generator, and sample holder. Neutral red dye was used to study the changes in the structure of cellulose by PEF pretreatment. Function generator drives the transistor present in the switching circuit; when pulse is applied by function generator to the switching circuit, switching circuit is turned on. Switching circuit is then transferred to the high voltage across the sample holder. So, by using function generator pulses of desired shape, width and high voltage can be applied to the sample. By using this setup, effects were observed on switch grass and wood. Results showed that at ≥8 kV/cm, switch grass showed high neutral red uptake. At low field strength, structural changes are less likely to occur. Electroporation through pulsed electric field is greatly affected by two parameters, pulse duration and electric field strength. Irreversible electroporation at >4 kV/cm with pulse duration in millisecond and ≥ 10 kV/cm with microsecond pulse duration was observed in Chlorella vulgaris which showed that pulse duration with a difference in micro- and milliseconds range can effect electroporation. Pulse electric field can increase hydrolysis rate by exposing cellulose to catalytic agents [40, 41, 46] (Figure 5).
\nPulse electric field (Intechopen.com).
In this pretreatment, acids are used to pretreat lignocellulosic biomass. The generation of inhibitory products in the acid pretreatment renders it less attractive for pretreatment option. Furfurals, aldehydes, 5-hydroxymethylfurfural, and phenolic acids are the inhibitory compounds that are generated in huge amount in acid pretreatment. There are two types of acid treatments based on the type of end application. One treatment type is of short duration, i.e., 1–5 min, but high temperature > 180°C is used, and the second treatment type is of long duration, i.e., 30–90 min, and low temperature < 120°C is utilized. Due to hydrolysis by acid treatment, separate step of hydrolysis of biomass can be skipped, but to remove acid, washing is required before the fermentation of sugars [43, 47]. For acid pretreatment, such reactors are required that show resistance to corrosive, hazardous, and toxic acids; therefore, acid pretreatment is very expensive. Flow through, percolation, shrinking-bed, counter current rector, batch, plug flow are different types of rectors that have been developed. For enhancing economic feasibility of acid pretreatment, recovery of concentrated acid at the end of the treatment is an important step.
\nTo treat lignocellulosic biomass, concentrated acids are also used. Most commonly used acids are sulfuric acid or hydrochloric acid. In order to improve the process of hydrolysis for releasing fermentable sugars from lignocellulosic biomass, acid pretreatment can be given. For poplar, switch grass, spruce, and corn stover, sulfuric acid pretreatment is commonly used. Reducing sugars of 19.71 and 22.93% were produced as a result of the acid pretreatment of Bermuda grass and rye, respectively. In percolation reactor, pretreatment of rice straw was carried out in two stages using aqueous ammonia and dilute sulfuric acid. When ammonia is used, 96.9% reducing sugar yield was obtained, while 90.8% yield was obtained in case of utilization of dilute acid. Eulaliopsis binate is a perennial grass and yielded 21.02% sugars, 3.22% lignin, and 3.34% acetic acid, and inhibitors in very less amount are produced when treated with dilute sulfuric acid [48, 49]. At 4 wt% concentration of sulfuric acid, pretreatment is preferred because of less cost and more effectiveness of the process. Dilute sulfuric acid causes biomass hydrolysis and then further breakdown of xylose into furfural is achieved. High temperature favors hydrolysis by dilute sulfuric acid [50]. Removal of hemicellulose is important to increase glucose yield from cellulose, and dilute sulfuric acid is very effective to achieve this purpose. It is necessary for an economical biomass conversion to achieve high xylan-to-xylose ratio. One-third of the total carbohydrate is xylan in most lignocellulosic materials. There are two types of dilute acid pretreatments, one is characterized by high temperature, continuous flow process for low solid loadings, and the other one is with low temperature, batch process and high solid loadings. Temperature and solid loadings for the first type are >160°C and 5–10%, respectively, and for the second type, temperature and solid loadings are around<160°C and 10–40%, respectively [51, 52].
\nBesides sulfuric acid and hydrochloric acid, other acids like oxalic acid and maleic acid are also used for the pretreatment of lignocellulosic biomass. Oxalic and maleic acids have high pKa value and solution pH as compared to sulfuric acid. Because of having two pKa values, dicarboxylic acids hydrolyze biomass more efficiently than sulfuric acid and hydrochloric acid. Other advantages include less toxicity to yeast, no odor, more range of pH and temperature for hydrolysis, and no hampering of glycolysis. Maleic acid has khyd/kdeg, due to which hydrolysis of cellulose to glucose is preferred over glucose breakdown. Effects of oxalic, sulfuric, and maleic acid pretreatment on biomass at the same combined severity factor (CSF) were determined [53]. The use of maleic acid produces high concentration of xylose and glucose as compared to oxalic acid.
\nApart from acids, few bases are also used for pretreatment of biomass. Lignin contents greatly affected the result of alkaline treatment. As compared to other pretreatment methods, alkali treatment requires less pressure and temperature and ambient condition, but alkali pretreatment needs time in days and hours. Degradation of sugar in alkali treatment is less than that by acid treatment, and also the removal and recovery of caustic salt are possible and easy in case of alkali treatment. Ammonium, sodium, calcium, and potassium hydroxides are used for alkaline pretreatment, but among these sodium hydroxide is the most commonly used alkaline pretreatment agent, whereas calcium hydroxide is the cheapest yet effective among all other alkali agents for pretreatment. By neutralizing calcium with carbon dioxide, calcium can be recovered easily in form of insoluble calcium carbonate. Using lime kiln technology, calcium hydroxide can be regenerated. Apparatus required for alkali pretreatment is basically temperature controller, a tank, CO2 scrubber, water jacket, manifold for water and air, pump, tray, frame, temperature sensor, and heating element. The first step of pretreatment consists of making lime slurry with water. The next step is spraying of this slurried lime on biomass; after spray, store the biomass for hours or, in some case, days. Contact time can be reduced by increasing temperature [54, 55, 56, 57]. Crystallinity index increases in lime pretreatment because of the removal of lignin and hemicellulose. Structural features resulting from lime pretreatment affect the hydrolysis of pretreated biomass. Correlation of three structural factors, viz., lignin, acetyl content and crystallinity, and enzymatic digestibility, was reported by Chang and Holtzapple [58]. He concluded that (1) regardless of crystallinity and acetyl content, in order to obtain high digestibility, extensive delignification is enough. (2) Parallel barriers to hydrolysis are removed by delignification and deacetylation. (3) Crystallinity does not affect ultimate sugar yield; however, it plays some role in initial hydrolysis. It is evident from these points that lignin content should be reduced to 10% and all acetyl groups should be removed by an effective pretreatment process. Thus in exposing cellulose to enzymes, alkaline pretreatment plays an important role. By increasing enzyme access to cellulose and hemicellulose and eliminating nonproductive adsorption sites, lignin removal can play its role in increasing effectiveness of enzyme.
\nAqueous organic solvents like methanol, acetone, ethanol, and ethylene glycol are used in this method with specific conditions of temperature and pressure. Organosolv pretreatment is usually performed in the presence of salt catalyst, acid, and base. The biomass type and catalyst involved decide the temperature of pretreatment, and it can go up to 200°C. Lignin is a valuable product, and to extract lignin this process is used mainly. Cellulose fibers are exposed when lignin is removed, which leads to more hydrolysis. During organosolv pretreatment, fractions and syrup of cellulose and hemicellulose, respectively, are also produced. There are certain variable factors like catalyst type, temperature, and concentration of solvent and reaction time which affects the characteristics of pretreated biomass like crystallinity, fiber length, and degree of polymerization. Inhibitor formation is triggered by long reaction, high temperature, and acid concentrations [59, 60]. In a study by Park et al. [61], effect of different catalyst was checked for the production of ethanol and among sulfuric acid, sodium hydroxide, and magnesium sulfate, and sulfuric acid was found to be most effective in ethanol production, but for enhancing digestibility the use of sodium hydroxide is proven to be effective. Sulfuric acid is a good catalyst, but its toxicity and inhibitory nature make it less favorite. Organosolv is not a cost-effective pretreatment process because of the high cost of catalysts, but it can be made cost-effective by recovering and recycling of solvents. Solvent removal is important because its presence effects fermentation, microorganism growth, and enzymatic hydrolysis. There is added risk of handling such harsh organic solvents. Acid helps in hydrolysis and depolymerization of lignin. Upon cooling lignin is dissolved in phenol, and in the aqueous phase, sugars are present. Formasolv involving formic acid, H2O, and hydrochloric acid is a type of organosolv in which lignin is soluble and at low temperature process can be carried out. For pretreatment with ethanosolv cellulose, hemicellulose and pure lignin can be recovered, but high pressure and temperatures are required when ethanosolv is used, and less toxic nature of ethanol as compared to other organosolv makes it favorite for pretreatment. Ethanosolv when used in pretreatment effects the enzymatic hydrolysis, so to prevent this low ethanol, water is used [62]. Recovery of ethanol and water reduces the overall cost of the pretreatment. For sugarcane bagasse Mesa et al. [63] used ethanosolv at 195°C for 60 min, and results showed formation of 29.1% sugars from 30% ethanol. Alcohol-based organosolv pretreatment is combined with ball milling by Hideno et al. [24] to pretreat Japanese cypress and observed a synergistic effect on digestibility. 50.1, 41.7, and 48.1% yield of organosolv pulping was obtained from ethylene glycol-water, acetic acid-water, and ethanol-water in a study done by Ichwan and Son [64]. Poplar wood chips were first treated with stream and then with organosolv to separate cellulose, lignin, and hemicellulose. About 88% hydrolysis of cellulose to glucose, 98% recovery of cellulose, and 66% increase in lignin extraction were reported by Panagiotopoulos et al. [65].
\nFor the pretreatment of lignocellulose, scientist took a great interest in using ionic liquids, for decades. Ionic liquids containing cations or anions are a new class of solvents with high thermal stability and polarity, less melting point, and negligible vapor pressure [66, 67]. Normally large organic cations and small inorganic anions compose ionic liquids. Factors like degree of anion charge delocalization and cation structure significantly effect physical, biological, and chemical ionic liquid properties. Interactions between ionic liquids and biomass get affected by temperature, cations and anions, and time of pretreatment.
\nIonic liquids actually compete for hydrogen bonding with lignocellulosic components, and in this competition disruption of network occurs. 1-Ethyl-3-methylimidazolium diethyl phosphate-acetate, 1-butyl-3-methylimidazolium-acetate, cholinium amino acids, cholinium acetate, 1-ethyl-3-methylimidazolium diethyl phosphate-acetate, 1-allyl-3-methylimidazolium chloride, and chloride are ionic liquids used for the treatment of rice husk, water hyacinth, rice straw, kenaf powder, poplar wood, wheat straw, and pine. Among other ionic liquids are imidazolium salts which are most commonly used [42]. 1-Butyl-3-methylimidazolium chloride is used for pretreatment by Dadi et al. [68] who observed a twofold increase in yield and rate of hydrolysis. For the pretreatment of rice straw, Liu and Chen [69] used 1-butyl-3-methylimidazolium chloride also known as (Bmim-Cl) and observed significant enhancement in the process of hydrolysis due to modifications in the structure of wheat straw by Bmim-Cl. Bmim-Cl played role in the reduction of polymerization and crystallinity. A twofold increase in hydrolysis yield from sugarcane bagasse was observed in a study by Kuo and Lee [70] as compared to untreated bagasse. 1-Ethyl-3-methylimidazolium-acetate is used in a study by Li et al. [71] for the pretreatment of switch grass in order to remove lignin at a temperature of 160°C for 3 hours. Results showed 62.9% lignin removal enhanced enzymatic digestibility, and reduced cellulose crystallinity was reported by Tan et al. [72] on palm tree pretreatment with 1-butyl-3-methylimidazolium chloride. Slight changes in composition of biomass occurred after ionic liquid pretreatments although significant changes were observed in the structure of biomass. Ionic liquid pretreatment is less preferred over other techniques because of high thermal and chemical stability, less dangerous conditions for processing, low vapor pressure of solvents, and retaining liquid state at wide range of temperature. Ionic liquids can be recycled easily and are non-derivatizing. Disadvantage of using ionic liquid pretreatment is that noncompatibility of cellulase and ionic liquids results in the unfolding and inactivation of cellulase. At less viscosity cellulose solubilizes at low temperature; that’s why while using ionic liquids, viscosity is an important factor to be considered regarding the energy consumption of the whole process. High temperatures trigger more side reactions and negative side effects like reducing ionic liquid stability [73].
\nOzone pretreatment is a great option for lignin content reduction in lignocellulosic biomass. In vitro digestibility of biomass is enhanced by the application of ozone pretreatment. Inhibitors are not formed in this pretreatment which is a great advantage because other chemical pretreatments produce toxic residues. In ozone pretreatment, ozone acts as an oxidant in order to break down lignin. Ozone gas is soluble in water and being a powerful oxidant, by breaking down lignin, releases less molecular weight, soluble compounds. Wheat straw, bagasse, cotton straw, green hay, poplar sawdust, peanut, and pine can be pretreated with ozone in order to degrade lignin and hemicellulose; however, only slight changes occur in hemicellulose, whereas almost no changes occur in cellulose. Ozonolysis apparatus consists of ozone catalytic destroyer, iodine trap used for testing efficiency of catalyst, oxygen cylinder, ozone generator, three-way valve, ozone UV spectrophotometer, pressure regulation valve, process gas humidifier, vent, and automatic gas flow control valve [40, 41, 74, 75, 76]. Moisture content hugely effects oxidization of lignin via ozone pretreatment as lignin oxidation decreases with increase in the moisture content of biomass. Ozone mass transfer is limited at less water concentration, which ultimately effects its reactivity with biomass. Longer residence time of ozone is caused by the blockage of pores by water film [77]. During ozonolysis, pH of water decreases because of the formation of organic acids. Alkaline media trigger delignification because it removes lignins that are bonded to carbohydrates [78, 79].
\nBiomass delignification is associated with the production of inhibitory compounds. Certain aromatic and polyaromatic compounds are produced as a result of delignification [80]. Structural changes in lignin are observed by Bule et al. [81] in a study; different lignin subunits showed aromatic opening and degradation of β-O-4 moieties in NMR analysis. How do aromatic structures of control- and ozone-pretreated samples differ? A spectrum showed a decrease in aromatic carbon signal concentration. Changes were observed in methoxy groups that suggest the breakdown of ester-linked structure. Different reactor designs are used for the ozone pretreatment of biomass, for example, batch reactor, Drechsel trap reactor, fixed bed reactor, rotatory bed reactor, and multilayer fixed bed reactor. Plug flow reactors are used by most researchers [82]. Heiske et al. [83] compared the characteristics of single layered and multiple layered bed reactors in order to improve the wheat straw conversion to methane. Straw with 16.2% lignin concentration was obtained from single layered reactor, whereas in multiple layered reactor, lignin concentration decreased up to 7.2% at the bottom layer. Due to wax degradation in ozone-pretreated wheat straw, production of fatty acid compounds is observed by Kádár et al. [84]. About 49% lignin degradation was observed when corn stover was pretreated with ozonolysis in a study by Williams [85].
\nAFEX technique belongs to the category of physicochemical pretreatment methods. In this low temperature process, concentrated ammonia (0.3–2 kg ammonia/kg of dry weight) is used as a catalyst. Ammonia is added to biomass in a reactor of high pressure; after 5–45 min of cooking, pressure is released rapidly. Normally temperature around 90°C is used in this process. Ammonia can be recovered and reused because of its volatility. The principle of AFEX is similar to steam explosion. Apparatus for AFEX includes reactor, thermocouple well, pressure gauge, pressure relief valve, needle valve, sample cylinder, temperature monitor, and vent. Rate of fermentation is seen to be improved by AFEX pretreatment of various grasses and herbaceous crops. For treatment of alfalfa, wheat chaff and wheat straw AFEX technology is used. Hemicellulose and lignin cannot be removed by using AFEX technology; hence, small amount of material is solubilized only. Degradation of hemicellulose into oligomeric sugars and deacetylation occur during AFEX pretreatment which is the reason of hemicellulose insolubility. After AFEX pretreatment of Bermuda grass and bagasse, 90% hydrolysis of cellulose and hemicellulose was achieved. Effectiveness of AFEX pretreatment decreases with increase in the lignin content of biomass, for example, newspaper, woods, nutshells, and aspen chips. In case of AFEX pretreatment for newspaper and aspen chips, maximum hydrolysis yield was 40% and 50%, respectively. So for the treatment of biomass with high lignin content, AFEX pretreatment is not a suitable choice.
\nAmmonia recycle percolation (ARP) is another method that uses ammonia. Aqueous ammonia (10–15 wt %) is used in this method. With a fluid velocity of 1 cm/min and temperature of 150–170°C and residence time of 14 minutes, aqueous ammonia passes through biomass in this pretreatment, and ammonia is recovered afterwards. Under these conditions, ammonia reacts with lignin and causes the breakdown of lignin breakdown linkages. Liquid ammonia is used in AFEX technique whereas in ammonia recycle percolation method/technique, aqueous ammonia is used.
\nIn this method, high-pressure saturated steam is used to treat lignocellulosic biomass, and then suddenly pressure is reduced, due to which lignocellulosic biomass undergoes explosive decompression. Initiation temperature of steam explosion 160–260°C and 0.69–4.83 MPa pressure is provided for few seconds to minutes, and then lignocellulosic biomass is exposed and retained at atmospheric pressure for a period of time; this triggers hydrolysis of hemicellulose and at the end explosive decompression, terminated the whole process. Cellulose hydrolysis potential increases due to the cellulose degradation and lignin transformation caused by high temperature. During the steam explosion pretreatment, acid and other acids formed, which played their role in the hydrolysis of hemicellulose. Fragmentation of lignocellulosic material occurs due to turbulent material flow and rapid flashing of material to atmospheric pressure [86, 87, 88]. In steam explosion pretreatment, the use of sulfuric acid or carbon dioxide decreases time, temperature, and formation of inhibitory products and increases hydrolysis efficiency that ultimately leads to complete removal of hemicellulose. Steam explosion pretreatment is not that effective for pretreating soft woods; however, acid catalyst addition during the process is a prerequisite to make the substrate accessible to hydrolytic enzymes. By using steam, targeted temperature can be achieved to process the biomass without the need of excessive dilution. Sudden release of pressure quenches the whole process at the end and also lowers the temperature. Particulate structure of biomass gets opened by rapid thermal expansion which is used to terminate the reaction. Steam explosion gets affected by certain factors like moisture content, residence time, chip size, and temperature. By two ways optimal hydrolysis and solubilization of hemicellulose can be achieved; either use high temperature and short residence time or low temperature and high residence time. Low energy requirement is a great advantage of steam explosion pretreatment, whereas in mechanical pretreatment 70% more energy is required as compared to steam explosion pretreatment in order to obtain the same, reduced particle size. So far steam explosion pretreatment with addition of a catalyst is tested and came closest to scaling up at commercial level due to its cost-effectiveness. In Canada, at Iogen demonstration plant, steam explosion pretreatment is used at a pilot scale. For hardwood and agriculture residues, steam explosion pretreatment is a very effective pretreatment process.
\nSupercritical carbon dioxide explosion treatment falls in the category of physiochemical pretreatment. Scientists had tried to develop a process cheaper than ammonia fiber explosion and a process which would operate at temperature lower than stream explosion temperature. In this process, supercritical carbon dioxide is used that behaves like a solvent. Supercritical fluids are compressed at room temperature above its critical point. When carbon dioxide is dissolved in water, carbonic acid is formed which causes less corrosiveness due to its special features. During the process, carbon dioxide molecules enter into small pores of lignocellulosic biomass due to its small size. Carbon dioxide pretreatment is operated at low temperature which helped in prevention of sugar decomposition by acid. Cellulosic structure is disrupted when carbon dioxide pressure is released which ultimately increased the accessibility of the substrate to the cellulolytic enzymes for the process of hydrolysis [11, 40, 41, 43]. Dale and Moreira [89] used carbon dioxide pretreatment for alfalfa and observed 75% theoretical release of glucose. Zheng et al. [90] performed experiments to show comparison among ammonia explosion, steam pretreatment, and carbon dioxide pretreatment of recycled paper and sugarcane bagasse. The results showed that carbon dioxide explosion pretreatment is cost-effective than AFEX.
\nHot compressed water is another terminology used for this method of treatment. High temperature (160–220°C) and pressure (up to 5 MPa) are used in this type of pretreatment in order to maintain the liquid state of water. However, chemicals and catalysts are not used in liquid hot water pretreatment method [42]. In this method, water in liquid form remains in contact with lignocellulosic biomass for about 15 min. In this treatment pressure is used to prevent its evaporation, and sudden decompression or expansion in this pretreatment process is not needed. This method has proved to be very effective on sugarcane bagasse, wheat and rye straw, corncobs, and corn stover. Different terms like solvolysis, aqueous fractionation, aquasolv, and hydrothermolysis are used by different researchers to describe this pretreatment method [42, 60, 91]. Based on biomass flow direction and water flow direction into reactor, liquid hot water pretreatment can be performed in three different ways. The first method is co-current pretreatment, which is carried out by heating biomass slurry and water at high temperature, holding it for a controlled residence time at pretreatment conditions, and finally applying cool environment. The second method involves the countercurrent pretreatment that engages pumping of hot water against biomass at controlled conditions. The third method is the flow-through pretreatment, which can be carried out by the flow of hot water through lignocellulosic biomass which acts like a stationary bed.
\nTo investigate the effect of liquid hot water pretreatment, a study was conducted by Abdullah et al. [92] that determined the different hydrolysis rates of cellulose and hemicellulose. Two steps of optimization of various conditions were considered. The first step was performed at less severity for hydrolyzing hemicellulose, whereas the second step was performed at high severity for cellulose depolymerization. Disadvantage of liquid hot water pretreatment is high energy consumption requirement for downstream process because of the involvement of large amount of water. However, the advantage of this process is that chemicals and catalysts are not required and no inhibitor is formed [60].
\nIn this pretreatment method, oxygen/air and water or hydrogen peroxide is used to treat biomass at high temperatures (>120°C) for half an hour at 0.5–2 MPa pressure [11, 93]. This pretreatment method is also used for the treatment of waste water and soil remediation. This method has proven to be very effective for pretreatment of lignin enriched biomass. Certain factors like reaction time, oxygen pressure, and temperature effect the efficiency of wet oxidation pretreatment process. Water acts like acid at high temperature, so it induces hydrolysis reaction as hydrogen ion concentration increases with increase in temperature which ultimately decreases the pH value. Pentose monomers are formed as a result of hemicellulose breakdown in wet oxidation pretreatment, and oxidation of lignin occurs, but cellulose remains least affected. There are certain reports on the addition of alkaline peroxide or sodium carbonate. The addition of these chemical agents help in bringing down temperature reaction and reduce the formation of inhibitory compounds. Efforts to improve the degradation of hemicellulose at high temperature lead to the formation of inhibitory compounds like furfural and furfuraldehydes. However, amount of the production of inhibitors in wet oxidation pretreatment is certainly less than that of liquid hot water pretreatment or steam explosion method. There is extremely less possibility of using this process at industrial scale because of two reasons. One is the combustible nature of oxygen, and the other is the high cost of hydrogen peroxide used in the process [94].
\nSPORL stands for sulfite pretreatment to overcome recalcitrance of lignocellulose, and this technique is used for pretreatment of lignocellulosic biomass [95]. SPORL is performed in two steps. The first step involves treatment of biomass with magnesium or calcium sulfite for the removal of lignin and hemicellulose fractions. The second step involves the reduction in size of pretreated biomass via mechanical disk miler. Effect of SPORL pretreatment was studied by Zhu et al. [22, 23] on spruce chips by employing conditions like temperature 180°C, half an hour time duration, 8–10% bisulfite, and 1.8–3.7% sulfuric acid. By employing these conditions, more than 90% substrate was converted to cellulose when cellulase of 14.6 FPU and 22.5 CBU β-glucosidase was used in hydrolysis. Low-yield inhibitors like hydroxymethyl furfural (HMF) (0.5%) and furfural (0.1%) were produced during this process. These percentages are far less as compared to acid-catalyzed steam pretreatment of spruce. In another study, SPORL-pretreated Popular NE222, beetle-killed lodgepole pine, and Douglas fir were purified. Low contents of sulfur and molecular mass were obtained with high phenolic derivative production [96].
\nSPORL pretreatment on switch grass with temperature ranging between 163 and 197°C, 3–37 min time duration, 0.8–4.2% sulfuric acid dose, and 0.6–7.4% sodium sulfite dose was performed by Zhang et al. [97]. The results with enhanced digestibility by the removal of hemicellulose due to sulfonation and decreased hydrophobicity of lignin were obtained. SPORL yielded 77.3% substrate as compared to 68.1% for dilute acid treatment and 66.6% through alkali pretreatment. When sodium sulfite, sodium hydroxide, and sodium sulfide were used in SPORL pretreatment of switch grass, an improved digestibility of switch grass was achieved. When SPORL treatment was applied with optimized conditions, 97% lignin and 93% hemicellulose were removed from water hyacinth, and 90% hemicellulose and 75% lignin were achieved for rice husk [98].
\nConventional methods for chemical and physical pretreatments require expensive reagents, equipment, and high energy. On the other hand, biological pretreatment requires live microorganisms for the treatment of lignocellulosic material, and this method is more environment friendly and consumes less energy. There are certain microorganism present in nature that exhibit cellulolytic and hemicellulolytic abilities. White-rot, soft-rot, and brown fungi are known for lignin and hemicellulose removal with a very little effect on cellulose. White rot is able to degrade lignin due to the presence of lignin degrading enzymes like peroxidases and laccases. Carbon and nitrogen sources are involved in the regulation of these degrading enzymes [41]. Cellulose is commonly attacked by brown rot, whereas white and soft rot target both lignin and cellulose contents of plant biomass. Commonly used white-rot fungi species are Pleurotus ostreatus, Ceriporiopsis subvermispora, Ceriporia lacerata, Pycnoporus cinnabarinus, Cyathus cinnabarinus, and Phanerochaete chrysosporium. Basidiomycetes species including Bjerkandera adusta, Ganoderma resinaceum, Trametes versicolor, Fomes fomentarius, Irpex lacteus, Lepista nuda, and Phanerochaete chrysosporium are also tested, and these species showed high efficiency for delignification [41, 99].
\nPretreatment of wheat straw was studied by Hatakka [100]. The results showed 13% conversion of wheat straw into sugars by Pleurotus ostreatus in duration of 5 weeks, whereas Phanerochaete sordida and Pycnoporus cinnabarinus showed almost the same conversion rate but in less time. For degradation of lignin in woodchips and to prevent cellulose loss, cellulase-less mutant of fungus Sporotrichum pulverulentum was developed [101]. Delignification of Bermuda grass by white-rot fungi Ceriporiopsis subvermispora and Cyathus stercoreus was studied that resulted in 29–32 and 63–77% improvement in delignification [102]. During the secondary metabolism in fungus P. chrysosporium, two lignin degrading enzymes, lignin peroxidase and manganese-dependent peroxidase, are produced in response to carbon and nitrogen limitation. Extracellular filtrates of various white-rot fungi contain these two enzymes.
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