Open access peer-reviewed chapter - ONLINE FIRST

MicroRNAs as Future Treatment Tools and Diagnostic Biomarkers in Alzheimer’s Disease

Written By

Heena Chauhan, Pawan Gupta and Bhagawati Saxena

Submitted: December 7th, 2021Reviewed: February 10th, 2022Published: April 23rd, 2022

DOI: 10.5772/intechopen.103173

IntechOpen
Alzheimer's DiseaseEdited by Montasir Elahi

From the Edited Volume

Alzheimer's Disease [Working Title]

Ph.D. Montasir Elahi

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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder and is considered to be the most common form of dementia. This disorder is characterized by the formation of amyloid β (Aβ) plaques, neurofibrillary tangles, and alterations in synaptic function, all of which cause memory loss and behavioral disturbances. Despite the high prevalence of AD, effective therapeutic and diagnostic tools remain unavailable. MicroRNAs (miRNAs, miRs) are regulatory non-coding RNAs that target mRNAs. MiRNAs are involved in the regulation of the expressions of APP and BACE1, Aβ clearance, and the formation of neuro-fibrillary tangles. Furthermore, there are evidences that show alteration in the expression of several miRs in AD. MicroRNA is emerging as a biomarker because they have high specificity and, efficiency, and can be detected in biological fluids such as cerebrospinal fluid, tear, urine, blood. Moreover, miRNAs may be acquired and measured easily by utilizing real-time PCR, next-generation sequencing, or microarray. These techniques are cost-effective in comparison with imaging techniques such as magnetic resonance imaging, positron emission tomography. These features make miRNAs viable therapeutic as well as diagnostic tools in the treatment of AD. This review covers the regulatory function of miRNAs in AD, as well as their prospective applications as diagnostic biomarkers.

Keywords

  • Alzheimer’s disease
  • dementia
  • pathogenesis
  • microRNAs
  • diagnosis
  • biomarker

1. Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder and is considered to be the most common form of dementia that majorly occurs in aged persons although a familial form of AD can occur in the younger population. Familial (early-onset) AD occurs due to mutations in the amyloid precursor protein (APP), presenilin 1, and presenilin 2 genes [1]. However, further identification of tau gene mutations in familial frontotemporal dementia (FTD) with chromosome 17 has shown a clear relationship between tau malfunction and dementia [2]. These findings show that AD and FTD are related in a hereditary spectrum of degenerative brain illnesses in which tau appears to play a key role [3]. Clinical manifestations of AD include a slow and persistent deterioration in memory, executive functions, and the capacity to carry out daily activities [4, 5]. Dementia affects around 36.5 million individuals worldwide in 2010. Every 20 years, the number of dementia cases is expected to roughly quadruple, reaching 65.7 million in 2030 and 115.4 million in 2050. AD is accounting for the preponderance of these dementia instances, accounting for 60–80% of all dementia cases [6]. Every year, an estimated 5–7 million new instances of AD are diagnosed in the elderly population [7]. In 2020, overall healthcare expenditures for AD treatment are predicted to be $305 billion, with expenditure expected to rise to more than $1 trillion as the population ages [8]. Even moderate developments in preventative and therapeutic techniques that postpone the initiation and advancement of AD can considerably lower the illness’s worldwide impact [9].

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2. Pathophysiology involved in AD

The scientific field dedicated for understanding the mechanisms involved in the progression of AD and developing relevant therapeutics is vast. Pathologically hallmarks of AD include the extra-neuronal clustering of Aβ plaques and the formation of intraneuronal neurofibrillary tangles (NFTs) which result in neuronal synaptic dysfunction [10, 11]. Aβ plaques formation is found in basal ganglia, amygdala, diencephalon, hippocampus, temporal and later it is found in the brain stem, cerebellar cortex and mesencephalon. The high levels of Aβ plaques are responsible for tau formation in the entorhinal, transentorhinal as well as locus coeruleus areas of the brain. It spreads to the hippocampus and neocortex in the critical stage [12].

Aβ plaque is formed from proteolysis of APP followed by two pathways (1) non-amyloidogenic pathway (physiological pathway), (2) amyloidogenic pathway (Figure 1). APP is a transmembrane glycoprotein whose a large portion toward the cytoplasm and a short portion inside the lumen. The non-amyloidogenic pathway prevents to the formation of toxic Aβ as APP is first cleaved by α-secretase and generates soluble fragments sAPPα and C83. These further cleaved by γ-secretase and produced non-toxic p3 and APP Intracellular Domain (AICD). On the other hand, the amyloidogenic pathway, neurotoxic Aβ formed through cleavage of APP by β-secretase (BACE1) followed by γ-secretase and formed sAPPβ, C99, Aβ, and AICD. These fragments are functionally active and influence or modulate signaling proteins [13]. Aβ oligomerization led to the formation of senile plaques and blockage the nerve transmission. There are mainly two types of Aβ isoforms soluble Aβ40 and insoluble Aβ42. The latter Aβ is more prone to aggregate and high concentration found in AD patients [14, 15]. The Aβ polymers aggregation results in blockage of ion channel, decreased energy metabolism, alteration in calcium homeostasis, diminish glucose regulation, and increases mitochondrial stress level, which further plays role in abnormality in neuronal health and causes neuronal death [12, 16]. Moreover, the AICD acts differently according to its generating pathways. The AICD from non-amyloidogenic pathways is degrading rapidly, but in the case of the amyloidogenic pathway, AICD behaves as a regulator for other genes [17].

Figure 1.

Amyloidogenic and non-amyloidogenic pathways. APP = amyloid precursor protein; ACID = APP intracellular domain; NFTs = neurofibrillary tangles.

Intra-neuronal deposition of NFTs are another pathophysiological hallmark of AD. NFTs were predominantly consisted of hyper-phosphorylated tau due to imbalance between phosphorylation and de-phosphorylation of tau [18]. Kinases are involved in the phosphorylation of tau protein, while phosphatases remove the phosphate residues. Tau proteins are microtubule-associated proteins that help vesicle transportation by stabilizing the microtubule. Microtubules are essential for axonal transport, neuronal structure, and neural plasticity [19]. Heavily phosphorylated tau may lose its capacity to stabilize itself and begin to self-form NFTs. Neurons cannot operate correctly without a full system of microtubules, and they eventually die. Tauopathies are considered to be an indicator of the severity of AD [20].

Figure 2.

Schematic diagram of miRNA synthesis; ago: argonaute protein; miRisc: RNA-induced silencing complex.

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3. MicroRNA

MicroRNA (miRNA/miR) is a kind of non-coding RNA that has 22–23 nucleotides. They regulate gene expression by interacting with the 3′-untranslated region (3′UTR) of mRNA. Thus, miRNA inhibits translation or destroys the targeted mRNA as a result of this event [21, 22]. Biogenesis of miRNA occurs with both canonical pathways as well as non-canonical pathways. However, miRNAs are processed dominantly by the canonical biogenesis pathway [23]. The detailed process of miRNA biogenesis by canonical pathway is illustrated in Figure 2. RNA polymerase II in the nucleus transcribed miRNAs gene to primary miRNAs (pri-miRNAs). In collaboration with Pasha/DGCR8, the RNase III enzyme, Drosha converts these pri-miRNAs into precursor miRNAs (pre-miRNAs) and then these pre-miRNAs are transported to the cytoplasm by Exportin 5 [24, 25]. These pre-miRNAs are of approximately 70 nucleotides in a hairpin structure. Pre-miRNAs features a hairpin loop structure that is identified by dicer present in the cytoplasm for cleavage, resulting in the formation of mature miRNAs which is a double-stranded miRNA duplex [25]. The miRNA-induced silencing complex (miRISC) is formed when one of these strands of the mature duplex is loaded onto a member of the Argonaute (Ago) family of proteins, whereas the other strand of the mature duplex is normally destroyed. RISCs mediate gene silencing by recognizing the 3′ untranslated region (3′ UTR) of target mRNA [24, 25].

Figure 3.

A schematic diagram of the Aβ hypothesis in AD pathogenesis and involvement of miRNA in each stage. The amyloid beta is produced as a result of processing the APP (amyloid precursor protein) by a sequential enzyme digescted by BACE1 and γ-secretase generate imbalance between the clearance and production of Aβ which is the key factor of AD.

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4. Association of microRNAs and Alzheimer’s disease

Pathologically, AD is generated by impaired metabolism of Aβ and the imbalance between the hyper-phosphorylated and de-phosphorylated forms of tau. Although these clinical-pathological features of AD are extensively established, therapies aiming at lowering synthesis or eliminating misfolded proteins are very limited [21]. Only four medicines, including three cholinesterase inhibitors (donepezil, rivastigmine, and galanthamine) and the glutamate regulator memantine, were licensed by the US Food and Drug Administration (FDA) for the treatment of cognitive impairment and dysfunction in symptomatic AD until June 2021. These symptomatic therapies can only delay rather than stop disease development [26, 27]. On June 7, 2021, Aducanumab, the first targeted Alzheimer’s therapy was approved by the FDA to treat patients with AD [27]. Thus, a different approach has centred on genetics, with several genes encoding proteins in central nervous system (CNS ) offered as candidates to explain AD etiology [21]. Earlier studies showed miRNA play role in the elaborating different types of pathogenic diseases including cardiovascular, cancer, and neurological disorders [28, 29]. Numbers of studies show the involvement of miRNAs in the pathogenesis and their therapeutic potential in various neurodegenerative diseases including AD, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Prion diseases [30, 31]. AD study indicates that miRNA may be helpful for the regulation of genes, expressions of proteins, and changes in phenotype in human diseases. Some research studies show the abnormal regulation of miRNA-dependent genes which are responsible for the formation and deposition of Aβ plaques as well as NFTs and consequently neuronal-degeneration [32, 33, 34, 35]. The focus of this review is the implication of the miRNAs in the two most well-recognized theories of AD pathogenesis: the Aβ hypothesis (Figure 3) and the tau hypothesis (Figure 4).

4.1 MicroRNAs involved in the regulation of APP expression

Although APP regulation is challenging, the research of regulatory processes indicate the prognosis of Alzheimer’s patients (Figure 3). Some scientific evidence shows that miR-106b regulates APP expression by binding on the 3′UTR region of APP [33]. The miR-101 [36], miR-16 [37], and miR-153 [38] are found APP negative regulators in in-vitro studies as well as in-vivo studies.

4.2 MicroRNAs involved in the regulation of BACE1 expression

It has been found that BACE-1 expression and activity are regulated by some miRNAs like the miR-29 family. BACE-1 expression level is increased with decreased expression of miR29a/b1 in sporadic AD brain. Moreover, it was also validated that low-level expression of miR29a/b1 is responsible for the pathogenesis of AD by promoting the production of Aβ plaques [39]. Another study found that downregulation of BACE1 is found in a cell line (SH-SY5Y) with overexpression of miR-29c via binding of BACE-13′ UTR [40]. Another study revealed that miR-107 regulates the expression of BACE1 in cell culture by binding the 3′UTR of BACE1 [41]. It was demonstrated that the BACE1 mRNA level was negatively affected by miR-107. Therefore, miR-107 could be a potential drug target [42] as it prevents the Aβ induced neurotoxicity and blood barrier dysfunction [43]. Certain miRNAs which are negative regulators of BACE1 expression by binding with 3′ UTR of BACE1 include miR-298/328 [44], miR-135a [45], miR135b [46], miR-186 [47], miR-195 [48], miR-200b [45], and miR-339-5P (Figure 3) [49].

Figure 4.

The imbalance between the hyper-phosphorylated and de-phosphorylated processes of Tau could lead to the formation of NFTs. The miRNAs involved in the phosphorylated and de-phosphorylated processes play a role in AD pathogenesis.

4.3 Role of MicroRNAs in Aβ clearance

The deposition of Aβ occurred due to an imbalance between production and clearance of Aβ. Several studies show that certain microRNAs are involved in the clearance of Aβ. The upregulation of miR-128 can alter the Aβ clearance by targeting the lysosomal enzyme system in monocytes of AD sporadic patients. The breakdown of Aβ plaque in Alzheimer’s patients improves when miR-128 is blocked in monocytes [50]. In addition, miR-34a was also involved in digesting the Aβ, thus improving the clearance of overexpressed Aβ [51]. miR-155, 154, 200b, 27b, 128 immune-related microRNA allegedly contribute to the process of Aβ clearance mediated by blood-derived monocytes (BDMs) when expressed variably in the CCL2/CCR2 (chemokine/chemokine receptor) axis [52]. miR-302 may attenuate Aβ induced neuronal toxicity in the brain of Alzheimer’s patients via PTEN/ AKT/Nrf2/Ho-1 pathway. miR-137 may reduced Aβ induced toxicity of neurons with the help of NF-kβ by TNFAIP1 expression repressing in N2a cells [53].

4.4 MicroRNAs targeting neurofibrillary tangles

The expression levels of miR 26b [54], miR-125b [55, 56], miR-138 [57], and miR-146a [58] have been shown to be considerably up-regulated while miR-132/212 down-regulated [59] in Alzheimer’s patients. Overexpression of miR-125b inhibited the two phosphatases i.e., PPP1CA and DUSP6 which further causes tau hyperphosphorylation while kinase expression/activity and tau phosphorylation were reduced when miR-125b was inhibited [55]. miR-146a was discovered to specifically target the coiled-coil containing protein kinase1 (ROCK1) in brain cells, and inhibiting ROCK1 might cause aberrant tau phosphorylation [58]. Reports showed that miR-138 was found to promote tau phosphorylation via directly targeting the retinoic acid receptor alpha (RARA)/glycogen synthase kinase-3b (GSK-3b) pathway in HEK293/tau and N2a/APP cells [57]. The increased levels of miR-26b in post-mitotic neurons led to the pathophysiology of AD via cell cycle entrance, tau hyper-phosphorylation, and death [54] (Figure 4).

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5. MicroRNAs as possible treatment tools in Alzheimer’s disease

The usage of miRNA in the treatment of the disorder is developing fast. In 2018, the FDA accepted the primary miRNA-founded therapy for the cure of the infrequent progressive polyneuropathy produced by hereditary transthyretin-mediated amyloidosis (hATTR) known as amyloid polyneuropathy [60]. The fact that miRNAs alter (or control) the expression of potential genes in AD has prompted researchers to pursue miRNA-based therapeutic options. The treatment modifications of miRNA are carried out in two different ways: first, the functioning of miRNAs is suppressed by oligonucleotides that target miRNAs are known as antagomirs while in a second way, synthetic oligonucleotides are used which plays the same role as endogenous miRNA (act as miRNA mimics) [61, 62]. Thus, a miRNA mimetic or antagonist could be evaluated as a treatment tool. It was also observed that increased miRNA expression can counter the accumulation of Aβ and tau in cell and animal models of AD. In transgenic mice model, the family of miR-200 (miR-200b and miR-200c) were recognized as Aβ secretion regulators by modulating mTOR in primary type of neurons [63, 64, 65]. The same effect of downregulation in Aβ production was seen after miR-330 upregulation in mice model of AD by activating the MAPK pathway [66]. In in-vitro AD model, inhibition of Aβ accumulation was observed by miR-15b by targeting enzyme BACE1 and NF-κB signaling [67]. Similarly, in-vitro studies suggested that miR-124 works as a basic regulating factor in process of AD by targeting BACE1 and controlling BACE1 gene expression [68]. To understand the contribution of miR-124 in the pathogenesis of AD, the brain tissues of 35 cases of sporadic AD and control subjects were analyzed for miR-124 expression by the qRT-PCR technique. The reduction in the level of miR-124 expression was seen in AD brain tissues with comparison to the control group. In addition, inhibition of miR-124 significantly increased BACE1 levels in human neuroblastoma cells (SH-SY5Y), while miR-124 overexpression significantly suppressed BACE1 [69]. MiR-219 was shown to be downregulated in severe primary age-related tau pathology as evaluated by the RT-qPCR study. In addition, it was shown in the Drosophila model (which produces human tau) that the reduction of miR-219 increases tau toxicity, while the overexpression of miR-219 partially reverses this effect [70]. In in-vivo studies for cognitive capacity in SAMP8 mice, it was found that the miR-214-3p suppresses the autophagy and apoptosis of hippocampus neurons in sporadic Alzheimer’s disease (SAD) [71]. It was also found that miR-let-7f-5p had anti-apoptotic and protective effect in Aβ induced neurotoxicity on grafted mesenchymal stem cells by targeting caspase-3 in AD model [72]. These findings suggested that miR-214-3p and let-7f-5p are having anti-apoptotic activity and increase the cell viability of neurons, therefore, it can be therapeutically important [71, 72]. One literature reported that NF-kB was inactivated by upregulation of PPAR-γ in mouse cortical neurons and Neuro2a cells. MiR-128 targeted the PPAR-γ and by targeting PPAR-gamma reduced the Aβ mediated cytotoxicity in the studies [73]. It was observed that overexpression of both miR-125b [55] and miR-146a [58] stimulates the apoptosis of neuron and tau phosphorylation in cellular and molecular AD models. In recent years many chemicals are studied that can affect miRNAs pharmacologically. Anti-inflammatory medications may be effective in preventing the course of AD through modulating miRNAs. Additionally, naturally obtained compounds are recognized for their possible effect as neuroprotective agents in AD, like resveratrol [74] and osthole [75], which appear to be effective by modulating a specific type of miRNA and activate processes like autophagy and neuronal regeneration. Exosomes, tiny vesicles generated by neurons and glial cells, may also be used as therapies to give miRNAs and/or short interfering RNA (siRNA) to patients, according to new research. Multitargeted treatment methods, such as the use of acetylcholinesterase (AChE) inhibitors in conjunction with the manipulation of certain miRNAs, are also being investigated. Approaching miRNAs as therapeutic targets has two major drawbacks: (1) their ability to control several transcripts (up to hundreds) at once, and (2) the difficulty of achieving effective miRNA delivery.

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6. MicroRNAs as possible diagnostic biomarkers in Alzheimer’s disease

AD is categorized, according to biochemical and clinical changes, into three different stages: pre-clinical i.e., early asymptomatic, mild cognitive impairment (MCI), and eventual dementia [76]. The majority of currently known biomarkers and approaches are focused on the late stages of the illness and may be categorized as follows: (1) neuropsychological tests, (2) neuroimaging techniques, and (3) protein biomarkers in the cerebrospinal fluid (CSF) [25]. Neuropsychological tests include cognitive assessments such as the Mini-Mental State Examination (MMSE) for early diagnosis to track cognitive changes over time and quantify the severity of cognitive impairment; however, this method is limited by factors such as the patient’s familiarity with the test and their educational attainment, which limits its sensitivity and specificity [77]. Neuroimaging examinations include fluorodeoxyglucose (FDG)-positron emission tomography (PET) and magnetic resonance imaging (MRI) for monitoring functional abnormalities as well as pathophysiological alterations such as medial temporal lobe atrophy and metabolic problems that can develop without evident cognitive impairment. Though this approach is viable, it has significant time and expense constraints. There are just a few laboratories that provide neuroimaging examinations. As a result, only a limited proportion of patients have access to neuroimaging [78]. Currently, protein biomarkers are the best biomarkers for monitoring AD and clinical research. They include Aβ1–40, Aβ1–4, phosphorylated tau (ptau), and total tau (t-tau) proteins in the CSF. However, a lumbar puncture is required to get CSF, which is invasive and not well tolerated by patients [78]. The identification of disease-causing genes is also a viable option. Simple, efficient, and inexpensive biomarkers for AD diagnosis are still lacking, especially in the early stages of the illness [25]. Several pieces of literature have found that particular miRNA species found in the biofluid of Alzheimer’s patients correlate with clinical alterations [22, 79, 80, 81]. Thus, miRNA emerges as a potential biomarker for initial diagnosis of AD as they are present in circulatory fluids which include CSF, seminal fluid, peritoneal fluid, amniotic fluid, pleural fluid, bronchial secretions seminal fluid, serum, plasma, and various other biological fluids [82, 83]. Circulatory miRNAs are a possible diagnostic biomarker for the illness because of their consistency and large quantity. miRNAs are when enwrapped in liposomes or attached to lipoproteins in the CSF, serum, or plasma, they are more stable and may endure harsh environmental conditions [84]. Furthermore, miRNAs may be acquired and measured with ease utilizing real-time PCR, next-generation sequencing (NGS), or microarray. Bio-molecules found in biological fluids such as CSF, tear, urine, and blood are being studied for their possible role in detecting disease progression in Alzheimer’s patients. According to previous research, miRNA is a modulator of the pathogenic state exhibited in AD [85]. Several miRNAs like miR-26b [54], miR-34a/c, miR125b, miR-210, and miR-146b are shown to change in blood and brain in Alzheimer’s patients, although the direction of changes is not always consistent between both miRNA sources [22, 86]. Furthermore, miRNA isolated from Alzheimer’s patients’ blood plasma and serum including miR-545-3p, miR-107, miR-15b-5p, miR-191-5p has been expected as potential AD biomarkers [22]. MiR-455-3p has emerged as a possible AD biomarker since growing levels in serum are commensurate with levels in AD brains, fibroblasts, lymphocytes, and even AD transgenic models [87]. This emerges the need to further explore the potential of a single miRNA to identify prodromal AD. A panel of miRNAs implicated in pathological processes underlying AD, such as neuroinflammation, has emerged as a diagnostic tool for AD prediction. While much work is being done on miRNA-based biomarkers for AD, few studies in the area have looked at the link between AD biomarkers and synaptic function modulation. Table 1 summarizes the most important findings in synaptic-related miRNAs obtained from circulating biofluids of AD patients and their potential value as biomarkers. The majority of studies have been done in blood samples, including serum and plasma, indicating a desire to investigate less invasive biomarkers. Certain studies reported earlier demonstrated that reproducibility between studies might be challenging even when miRNAs are obtained from the same sample source. As an example, the drop in miR-132 in serum from mild cognitive impairment (MCI) and AD patients [102, 107], has been replicated in plasma sample [131], although Sheinerman and team found an increase in MCI individuals [105], MiR-132, along with miR-206, which is similarly downregulated in MCI serum, has been proposed as part of a serum-based signature for MCI identification [102]. The adoption of miRNA-based signatures, which take into account the simultaneous modification of many miRNAs, can result in greater accuracy, sensitivity, and specificity values, which could be beneficial for future diagnostic tools. Another signature based on serum-miRNA levels, including synaptic-related miR-23a, miR-29a, and miR-125b has shown promising results in distinguishing Alzheimer’s patients from healthy cognitive controls (HCC) [92]. Although results are inconsistent between researches, the diagnostic usefulness of the miR-29a/b family has been examined in serum and CSF [39, 92, 96, 100, 132]. The modification of these miRNAs in biological fluids during AD pathology appears to be obvious. MiR-125b and miR-23a, on the other hand, have continuously increased in serum, demonstrating a strong ability to differentiate between AD and control participants [92, 115]. MiR-125b’s potential has also been investigated in CSF, where it has subsequently been offered as a specialized tool [116]. As previously reported, an increase in associated miR-125a levels has been seen in CSF from AD patients, suggesting that it might be used as a biomarker [100, 107]. Limited literature has looked at miRNA levels over time to see whether they might predict the development of MCI into AD. Beneficial diagnostic tool for classify MCI from AD include miR-206 [103], miR-146a, and miR-181a [113], miR-181c [88, 92], miR-181a and miR-181c [105], miR-92a-3p, and miR-210-3p [86], miR-107 [133].

TargetmiRNAFunctionBio-fluidsUpregulation (Up) or Downregulation (Down)References
APPmiR-106bRegulate APP expressionSerumUp[33, 88, 89]
miR-101Negative regulator of APP expressionSerumUp[36, 89, 90]
miR-16Decreased expression of miR-16 lead to accumulation of APP protein in ADBloodUp[37, 91]
ADAM10miR-23aNon-amyloidogenic APP processingSerumUp[92, 93]
miR-107PlasmaDown[41, 94]
miR-451Plasma-derived extracellular vesiclesDown[93, 95]
BACE1miR-9TNF-α,ephrin-A2 and APP cleavageCSF exosomesUp[96, 97, 98, 99]
Serum
miR-107PlasmaDown[41, 94]
miR-29aSerumUp[39, 96, 100]
CSF
miR-29bSerumUp[39, 96, 101]
CSFDown
BDNFmiR-206Growth factor involved in synapse maturationSerum and plasmaUp[102, 103, 104]
CREB1miR-134Transcription factor involved in synaptic plasticityPlasmaUp[105, 106]
DLG4miR-125aScaffold protein (PSD-95)CSF and SerumUp[107, 108]
DPYSL2miR-181cAxon guidance (CRMP-2)PlasmaUp[86, 98, 109]
SerumDown[96]
EFNA3miR-210(Ephrin-A3) Axon guidancePlasmaUp[86, 110]
GRIA1miR-137Synaptic transmissionSerumDown[96, 111]
miR-501SerumDown[78, 112]
GRIA2miR-181aNeurotransmitter releaseBloodUp[113, 114]
GRIN2AmiR-125bSynaptic transmissionCSF and SerumDown[115, 116, 117]
GRIN2BmiR-34aSynaptic transmissionPlasmaUp[101, 118, 119]
CSFDown
IGF1miR-26bGrowth factor involved in synapse maturationSerumUp[116, 120, 121]
Blood
MME (NEP)miR-26bNeurite outgrowthSerumUp[116, 121, 122]
Blood
SYNmiR-106bInhibit tau phosphorylationSerumUp[88, 89, 123]
STIM2miR-128NMDA-evoked intracellular Ca2+PlasmaUp[105, 124, 125]
SIRT1miR-132Acetylation of substrates related to learning and memorySerumDow[93, 102]
SYT1miR-146aTrafficking/neurotransmitter releaseBloodUp[21, 113, 126]
CSF and plasmaDown[101]
TMOD2miR-191Actin filament organizationPlasmaDown[127, 128]
VAMP2miR-34cNeurotransmitter release VesiclePlasmaUp[129, 130]

Table 1.

Changes in the level of MiRNAs in the blood, plasma/serum and cerebral-spinal fluid (CSF) of AD patients with their targets and functions.

The potential utility and benefits of miRNAs as early biomarkers for AD underscore the urgent need for protocol standardization as a critical tool for accelerating development in generating more accurate findings and bringing breakthroughs to the clinics. Molecular diagnostics companies like DiamiR are already developing and commercializing miRNA-based technologies, demonstrating the progress made in the field and the real possibilities of using miRNAs as biomarkers for AD not only in screening and diagnosis but also as a useful tool for bettering the condition of clinical trial participants.

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7. Conclusion

MiRNAs play an important role in the progression of AD. Alzheimer’s investigation indicates that miRNA may assist to gene regulation, protein-protein expressions, and phenotypic changes in diseases condition and some indication shows that aberrant regulation of miRNA-dependent genes are related to some cellular and molecular events which are liable for Aβ production, neurodegeneration, and NFTs formation. This review highlights the involvement of miRNAs in the regulation of APP expression, BACE1 expression and Aβ clearance. Thus, miRNA is possibly used as a treatment tool for AD. In addition to the therapeutic tool, microRNAs are also emerging as diagnostic tools because of their high sensitivity, efficiency, and specificity. It is found in biological fluids like CSF, extracellular fluid, pleural fluid, seminal fluid, bronchial secretions, breastmilk, serum, blood, plasma, etc. Thus, given the intricacy of AD development, illness history, and diagnosis, future treatment methods such as miRNA and anti-miRNA (antimiR, antagomir) techniques are needed:

  1. It will be coupled with improvements in the development of sensitive and precise neuroimaging and biofluid-based diagnostic tools for miRNA and other AD-relevant biomarkers,

  2. It will need to be simultaneous and multimodal, addressing numerous disease pathways, and neurological symptoms to block basic illness progression while minimizing ancillary off-target consequences,

  3. It will be used for screening in conjunction with basic medical care and as a second level diagnostic work-up for expert diagnosis and clinical treatment,

  4. It may entail correct medication therapy and distinct therapeutic development within the neurophysiological perspectives and the systems biology.

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Conflict of interest

The authors declare no conflict of interest.

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Abbreviations

3’UTR3′-untranslated region
AChEacetylcholinesterase
ACIDAPP intracellular domain
ADAlzheimer’s disease
ADAM10a disintegrin and metalloproteinase 10
Agoargonaute protein
AKTprotein kinase B
APPamyloid precursor protein
amyloid beta
BACE1β-site amyloid precursor protein cleaving enzyme 1
BDMsblood-derived monocytes
C83proteolytic products of APP
CCL2/CCR2chemokine (c-c motif) ligand 2/chemokine (c-c) receptor type 2
CREB1CAMP responsive element binding protein 1
CSFcerebrospinal fluid
DGCR8DiGeorge syndrome critical region 8
DLG4discs large homolog 4
DPYSL2dihydropyrimidinase-related protein 2
Drosharibonuclease III enzyme
DUSP6dual specificity phosphatase 6
EFNA3ephrin A3
Evsextracellular vesicles
FDGfluorodeoxyglucose
FTDfrontotemporal disorder
GRIA1glutamate receptor 1
GRIN2Bglutamate receptor ionotropic, NMDA 2B
GSK-3bglycogen synthase kinase-3β
hATTRhereditary transthyretin-mediated amyloidosis
HCChealthy cognitive controls
HEK293human embryonic kidney cell-line
Ho-1heme oxygenase 1
IGF1insulin-like growth factor 1
MAPKmitogen-activated protein kinases
MCImild cognition impairment
MEF2Dmyocyte-specific enhancer factor 2D
MME (NEP)membrane metalloendopeptidase (neutral endopeptidase)
MMSEmini-mental state examination
MRImagnetic resonance imaging
mTORmammalian target of rapamycin
N2aneuro-2-a cell
NF-kβnuclear factor kappa beta
NFTsneurofibrillary tangles
NGSnext-generation sequencing
Nrf2nuclear factor erythroid 2-related factor 2
PETpositron emission tomography
PPARperoxisome proliferator- activated receptor gamma
PPP1CAPP1-alpha catalytic subunit gene
pri-miRNAsprimary miRNAs
PTENphosphatase and tensin homolog
RARAretinoic acid receptor alpha
RISCRNA-induced silencing complex
ROCK1Rho-associated, coiled-coil-containing protein kinase 1
SADsporadic Alzheimer’s disease
SAMP8senescence-accelerated mouse prone
sAPPsoluble amyloid precursor protein
SH-SY5Yhuman derived neuroblastoma cell line
siRNAsmall interfering RNAs
SIRT1silent mating type information regulation 2 homolog
STIM2stromal interaction molecule 2
SYN2synapsin II
SYT1synaptotagmin-1
TMOD2tropomodulin 2
TNFAIP1TNF alpha induce protein 1
VAMP2vesicle-associated membrane protein 2

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Written By

Heena Chauhan, Pawan Gupta and Bhagawati Saxena

Submitted: December 7th, 2021Reviewed: February 10th, 2022Published: April 23rd, 2022