Descriptive and comparative statistics of anthropometric data of elite and non-elite beach volleyball athletes - 2018 stage.
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In the sportive competitions elite and not elite athletes have a demand for significant results. Therefore, the use of scientific methods is a current practice, in the sense of helping in the development of the sport performance and consequently in the sport results of these athletes. The characteristics that constitute the variables of the anthropometric profile of an athlete may be reflected in a way that he/she may play a determining role in his/her sporting potential within the chosen modality, which may lead to success [1]. Thus, the stature for athletes of the beach volleyball, can be important to contribute in the defensive and offensive actions of the modality, it is necessary, however a verification of the anthropometric profile to establish standards with relation to the modality [2]. We can affirm that the anthropometric profile of an athlete can influence in its more adequate sport performance for that modality [2]. However, anthropometric parameters are not the only determining variable in beach volleyball, as there are also cognitive factors in all its parameters, decision making, attention levels, working memory, which are fundamental in a sport with a great variability and impressibility [3, 4, 5, 6]. The neurocognitive mechanisms in sport and the motor skills developed involve several neural processes, in addition to the learning of sport techniques. There are four elements that stand out with the development and neural adaptations of elite athletes [7]. (1) neural efficiency, which in turn is linked to a smaller amplitude in relation to the neuroelectric activity, causing a lower brain energy expenditure (2) referring to a larger cortical expansion, which is linked to motor and sensorial skills (3) specialized processing occurs in specific brain regions, which are developed through sports experiences lived by athletes, which induces the automation of neuroelectric connections (4) internal models, which cause the athlete to mentally simulate sports situations to which he/she will be submitted [7, 8]. These adaptations, for the most part, are considered to be motor areas, in brain regions that aid sport development, especially the cognitive engagement that is involved in sporting actions [9]. Cognitive processes trigger the so-called decision-making, being this decision-making composed of underlying elements such as attention, memory, perception and anticipation [6, 10] these cognitive factors are linked to sport. So the performance of the athlete to which he is dedicated will always depend on his physical and cognitive actions [11]. Elite athletes when compared to non-elite athletes, in several review studies demonstrate superior cognitive performance in specific situations of their sports [12]. Based on the perspective that these elements have repercussions on the performance of these individuals and on their sporting performance, the following objective of the study arises: to compare the variables of anthropometric profile and cognitive performance, between elite and non-elite athletes of the sport of beach volleyball?
This research had a descriptive characteristic [13] which verified the anthropometric profile and cognitive performance among elite and non-elite athletes of the beach volleyball modality. The universe of the study was constituted by athletes of the national circuit of beach volleyball/Banco do Brazil and the Cabo Branco Beach Volleyball Training Center/CT Cangaço. The sample was composed by 8 athletes, selected by non-probabilistic procedure, of the intentional type, with age bracket between 18 and 35 years old, being 04 elite athletes and 04 non-elite athletes. The participants received an informative document with all the procedures performed in the research. Afterwards, an informative document containing all the details regarding the date, time and place of research was delivered. Athletes who did not present the Free and Informed Consent Term - TCLE; did not agree with the terms of commitment, assumed with the researcher; were under medication treatment that influenced the execution of the tests; those who refused to participate in the study as volunteers, with no return or financial advantage, and those who did not show up on the day of data collection, were excluded from the process. The present study complied with the norms for research with human beings, resolution 466/12 of the National Health Council. CAAE: 26950119.0.0000.5176. One of the CogState® Computerized Cognitive Test Battery (Brief Battery) was used in the evaluation of cognitive performance, which is composed of four tests: Detection Test (cognitive domain measured: Psychomotor Function) Figure 1, Identification Test (cognitive domain measured: Attention) Figure 2, One Card Learning Test (cognitive domain measured: Visual Learning), One Back Speed Test (cognitive domain measured: Working Memory) in the study conducted used 4 tests from the (Brief Battery/Brief Battery) being they Detection (Simple Reaction Time); Identification (Choice Reaction Time); One Back Speed (Working Memory); One Back Acuracy (Short Term Memory) which presented results in milliseconds (ms) and logarithmic values normalized to base 10, with validity from 0.76 to 0.89 [14, 15]. It was necessary to perform a demonstration of the protocol to facilitate the understanding and learning of the test. The analysis was done by the quantitative number of positive and negative answers divided by the total number of attempts executed.
Detection test.
Identification test.
Such results will be presented as percentage of correct answers. For weight evaluation a Tanita® Bc 601 bioimpedance scale was used, the individual barefoot with legs slightly apart with arms at the side of the body with the most erect body possible. For height assessment, a
In Table 1 the anthropometric profile of elite and non-elite beach volleyball athletes were observed and it was verified that there was a significant difference in the variable age (sig = 0.029).
Profile | Veriables | Elite (n = 4) | Non-Elite (n = 4) | Comparison | |||
---|---|---|---|---|---|---|---|
Anthropometric | Med | Min_Max | Med | Min_Max | Mann–Whitney U | Sig. | |
Age | 32,50 | 30,00_34,00 | 19,25 | 18,00_20,00 | 0.29 | ||
Weight | 94,46 | 85,00_102,85 | 88,50 | 78,00_110,00 | 0.114 | ||
Height | 1,98 | 1,85_2,10 | 1,89 | 1,79_1,93 | 0.200 |
Descriptive and comparative statistics of anthropometric data of elite and non-elite beach volleyball athletes - 2018 stage.
In Table 2 the cognitive performance of elite and non-elite beach volleyball athletes was observed and it was verified that there were significant differences in the variables: Detec (0.029); Ident (0.029); evaluated by the CogState® computerized test battery (Brief Battery).
Performance | Variables | Elite (n = 4) | Non-Elite (n = 4) | Comparison | |||
---|---|---|---|---|---|---|---|
Cognitive | Med | Min_Max | Med | Min_Max | Mann–Whitney U | Sig. | |
DETEC | 114,5 | 113,00_116,00 | 102,5 | 89,00_110,00 | 0.29 | ||
IDENT | 115,5 | 114,00_117,00 | 106,5 | 99,00_111,00 | 0.29 | ||
OBS | 107,25 | 96,00_113,00 | 101,5 | 93,00_112,00 | 0.200 | ||
OBA | 96,25 | 85,00_102,00 | 91,75 | 70,00_102,00 |
Descriptive and comparative statistics of Cognitive Performance (CogState®) of elite and non-elite beach volleyball athletes - 2018 Stage.
DETEC. = Detection; IDENT. = Identification; OBS. = One Back Speed; OBA. = One Back Acuracy.
The results presented in this study showed significant difference in the variable of anthropometric profile age (sing = 0.029), in elite and non-elite athletes of beach volleyball (Table 1). According Guedes [16] states that the chronological age and age defined by the birth of an individual that is determined by the civil calendar, thus the difference between the two groups is simply chronological. With the data of the above presented variables, there is a need that during a process for a selection of athletes for the Beach Volleyball modality, especially in relation to one of the variables the height, it can be observed a certain evolution, where it demonstrates that the stature inside of the anthropometric profile and a main measure for a selection process of this modality [17]. According to Gabbett, Georgieff and Domrow the anthropometric profile characteristic of the variable height is of fundamental importance for the performance of attack and blocking that occur during a beach volleyball game. In the variable of the anthropometric profile with relation to the weight of the elite athletes and not elite of the beach volleyball, with the variations, it can have or not a negative association for accomplishment of some tasks to be accomplished in the beach volleyball modality [1, 2]. When analyzing the cognitive performance of elite and non-elite beach volleyball athletes (Table 2) in the overall score in the variables where these results are given through the speed in milliseconds (ms) that are logarithmic values normalized to base 10, with validity from 0.76 to 0.89: Detection (Simple Reaction Time); Identification (Choice Reaction Time); One Back Speed (Working Memory); One Back Acuracy (Short Term Memory); evaluated by the CogState® computerized test battery (Brief Battery). It was verified in (Table 2) that significant differences occurred in the analyzed variables: Detection (Simple Reaction Time); Identification (Choice Reaction Time); evaluated by the CogState® computerized test battery (Brief Battery). When analyzing the variables: detec (sing = 0.029), ident (sing = 0.029), we can observe that elite athletes, have a better cognitive performance, in relation to non- elite athletes in these two variables, once, in the test results of these two variables, they are classified in a lower score as better performance. Where the variable (Detec) has its cognitive domain the (attention) and the variable (Ident) has its cognitive domain the (psychomotor function) since we analyzed the cognition of the greatest athletes of beach volleyball in Brazil and the world, being these world and Olympic champions of this category. According to Santos [18]. The processes of perception and attention depend on some factors, among them, the conscious ability to select the most essential sources of information and the quantity of stimuli. For SCHMIDT (1993) the concept of attention is related to the “information processing capabilities that put limits on the skillful human performance”. Baddeley and Hitch in [19]. postulated a theory that supports the main current on (Working Memory) from an assumption that (Working Memory) has a command center, which is the Central Executive System (CES), responsible for integrating new information with data stored in long-term memory [20]. Several studies show that the (Working Memory) is one of the last cognitions to consolidate, but also one of the first to suffer degeneration in brain structures, being the frontal lobe the most affected bringing cognitive losses [21, 22]. In view of these facts, it is necessary to research about the importance of these variables to improve the performance of these athletes.
Analyzing the anthropometric parameters and the cognitive variables, it was observed that there was significant difference, in the anthropometric profile in the variable age (sig = 0.029) and in the cognitive performance, significant differences occurred in the variables Detec (sig = 0.029) and Indent (sig = 0.029) where in these two variables the elite athletes have a better cognitive performance than the athletes no elite.
Own financing.
There is no conflict of interest between the authors.
Research project presented to the Pro-rector of Postgraduate Studies at Specialization Level of the Physical Education Course of the University Center of João Pessoa - UNIPÊ, in compliance with the requirements of the Work of Course Completion, taught by
Alzheimer’s disease (AD) is the most recurring chronic and incurable neurodegenerative disorder. The main neuropathological findings on AD are beta-amyloid protein plaque (APP) deposition, an accumulation of hyperphosphorylated neurofibrillary tangles, inflammation, neurotransmitter signaling dysregulation, brain atrophy, and neuronal changes. AD affects the central nervous system (CNS) and results in an impaired emotional state, loss of synapses, neuronal death, and progressive cognitive decline. Some risk factors such as advanced age, genetic factors, and head trauma (among others) are involved in AD progression. Alzheimer’s disease is responsible for marked morbidity and mortality due to the difficulty in treatment and irreversible damage. However, there is condition stabilization in some cases, and the individual can postpone their life expectancy for years [1].
\nNicotinic acetylcholine receptors (nAChR) are involved with neuroprotective effects in AD. Furthermore, nAChR agonists and antagonists have been shown to have positive effects on memory. Cotinine and methyl cyclonite are examples of nAChR ligands associated with brain protection when in vitro and in vivo tests have been performed. In addition, nAChR and the muscarinic acetylcholine receptor family (mAChR) are acetylcholine targets in the brain. The nAChR family is affected in AD because beta-amyloid peptides (Aβ) can interact with these receptors [1]. Acetylcholine (Ach) plays a crucial role in CNS. Choline acetyltransferase enzyme is responsible for ACh synthesis from acetyl-CoA and choline in the cytoplasm. The acetylcholine vesicular transporter absorbs the neurotransmitter in synaptic vesicles. After depolarization, ACh undergoes exocytosis in reaching the synaptic cleft, where it can bind with its receptors. The ACh in the synaptic cleft is readily hydrolyzed by the acetylcholinesterase enzyme, forming acetate and choline, which is recycled at the presynaptic nerve terminal by the high-affinity choline transporter. Cholinergic neurons located in the basal forebrain, including the neurons which form Meynert’s basal nucleus, are severely affected in AD. The loss of cholinergic neurons contributes to memory and attention deficits. Therefore, drugs acting on the cholinergic system represent a promising option for treating AD patients [2]. The conventional therapeutic prescription for AD consists of three acetylcholinesterase inhibitors and one NMDA receptor antagonist. Researchers around the world are developing new nAChR agonists to develop drugs with lower risks and adverse effects [3].
\nAnother important target in AD is the estrogen receptor (ER), which may represent a promising therapeutic approach since its activation through agonists prolongs survival, improves spatial recognition memory, and decreases the amyloid pathology progression in animal models of AD. On the other hand, estrogen receptor genetic polymorphisms have been associated with cognitive impairment, accelerated brain aging, and increased risk of AD, predominantly in women. A methylation promoter in estrogen receptor α is also related to impaired cognitive function and quality of life in AD patients by inhibiting ERα mRNA expression and transcription [4]. Estrogen can increase neural plasticity, cognitive functions, and the brain’s regenerative potential. The beneficial effects of estrogen on neural plasticity occur at three levels: cellular, morphological, and synaptic function. Studies have shown that estradiol can increase neurogenesis in several brain regions, such as the hippocampal gyrus. These estrogen-induced hippocampal neurons contribute to learning and memory. Estradiol can also rapidly increase the number of dendritic spines in the hippocampus, amygdala, and hypothalamus and thus improve the performance in a hippocampal-dependent memory task. Moreover, estradiol is an effective enhancer of synaptic transmission in the hippocampal system. Estradiol plays an important role in promoting neurogenesis and neuronal plasticity to maintain healthy cognitive function and protect against women’s cognitive decline during aging [5]. Therefore, estrogen with selective effects on ERα or G protein-coupled estrogen receptors (GPER1 or GqMER) can be used to influence the inflammation process resolution, with positive effects on AD progression [6].
\nRyanodine receptors (RyR) are an ion channel family responsible for calcium release from intracellular reserves during muscle contraction. Calcium homeostasis is known to be related to cognition; thus, RyR may be associated with AD, especially RyR 3, which is found in various nervous system areas. In addition, RyR 1 and RyR 2 are also found in the brain, although they are not predominantly present in the nervous system. Ryanodine receptors can be regulated by several proteins and ions, as well as redox modifications. Antioxidants importantly prevent cognitive decline, long-term depolarization, and memory loss by inhibiting RyR sensitization [7]. Calcium-dependent signaling pathways are related to AD pathogenesis. A pharmacological approach (using a RyR stabilizing drug) or gene therapy of calcium leakage (mediated by RyR2) improved synaptic plasticity, and behavioral and cognitive functions and reduced Aβ loading. Genetically, altered mice (congenital leaking of RyR2) exhibited premature and severe defects in synaptic plasticity, and behavioral and cognitive function. These data provide an underlying mechanism for RyR2 channels, which can be considered as possible therapeutic targets in AD [8]. Additionally, calcium accumulation may result in the calpain and CaMKK2 activation, contributing to Aβ production and tau phosphorylation. Ryanodine receptor dysfunction can also lead to abnormal activation and accumulation of PKR kinase in AD brains. PKR kinase is linked to calcium accumulation and PKR autophosphorylation can be triggered by Aβ peptides in neuronal cultures in a calcium-dependent manner. In turn, PKR activation may lead to Aβ production by regulating BACE1 levels and abnormal tau protein phosphorylation by GSK3 activation. Dantrolene, a RyR inhibitor, may be an AD treatment [9].
\nGamma-Aminobutyric Acid receptor (GABAR) inhibition is also related to a better prognosis in AD. Gamma-Aminobutyric Acid receptor regulates learning, memory, and cognition, inhibits Adenylyl Cyclase and the cAMP cascade, as well as controls GABA and glutamate release. CGP35348 is a GABA receptor antagonist, and the CGP35348 hippocampal concentration is a crucial point for improving memory by reducing APP toxicity. Several neurological and psychiatric disorders occur with neuronal hyperexcitability in specific regions of the brain or spinal cord, partly due to some loss and/or dysfunction of GABAergic inhibitory interneurons [10]. Strategies which improve inhibitory neurotransmission in the affected brain regions may decrease deficits associated with these disorders. This perception has prompted an interest in testing the efficacy of GABAergic interneuron grafting in the brain or spinal cord regions which exhibit hyperexcitability, GABAergic interneurons scarcity, or impaired inhibitory neurotransmission, using preclinical models of neurological and psychiatric disorders [10]. Defective GABAergic neuronal functions can lead to cortical network hyperactivity and aberrant neuronal oscillations and thereby generate a detrimental change in memory processes [11]. In this context, GABAergic cell therapy may decrease neurological deficits in AD preclinical models [10]. Alzheimer patients have low GABA levels in the brain and spinal cerebrospinal fluid (SCF), and these changes are more severe in ApoE4 allele carriers. ApoE4 is associated with increased brain activity at rest and memory tasks, possibly reflecting impaired GABAergic inhibitory control. In addition, GABA levels in human SCF change with aging, constituting the strongest AD risk factor. Therefore, ApoE4 may at least partially contribute to the AD pathogenesis, causing age-dependent impairment in GABAergic interneurons [12].
\nThe relationship between the receptor for advanced glycation end products (RAGE) and AD has also recently been established; RAGE is widely expressed and regulated in the AD brain. Furthermore, RAGE is involved with the transport of beta-amyloid protein through the blood-brain barrier (BBB) to the brain parenchyma. Interactions between RAGE and APP result in inflammatory responses and oxidative stress, as well as reduce cerebral blood flow. The receptor also inhibits the elimination of APP and RAGE ligands such as AGE, HMGB1, and S100β, which are involved in the neurodegenerative disease progression. Additionally, RAGE/AGE interactions induce the apoptosis cascade and neuronal inflammation [7]. In addition, RAGE has been considered as a therapeutic approach in AD; in fact, a RAGE antagonist demonstrated a protective effect in an animal model. Chronic oral dosing of PF-04494700 antagonist in transgenic AD mice reduced Aβ levels, improved performance in spatial memory testing, and normalized the electrophysiological recordings of hippocampal slices. According to the results of the Phase II clinical study [13], the RAGE inhibitor has an excellent safety profile and is well-tolerated for over 10 weeks in patients with oral AD. These inhibitors block the binding of Aβ peptides to the RAGE V domain as well as inhibit the cell stress induced by Aβ in cells expressing RAGE in vitro, as well as in the brains of mice [14].
\nMoreover, a RAGE inhibitor (FPS-ZM1) has no animal toxic activity and easily crosses the BBB. In aged mice with AD, FPS-ZM1 can inhibit the RAGE-mediated influx of Aβ40 and Aβ42 in the brain. FPS-ZM1 binds exclusively to RAGE in the brain, inhibiting Aβ production and suppressing microglia activation and neuroinflammatory response. Blocking RAGE actions in the SCF and brain normalizes cognitive performance and cerebral blood flow. FPS-ZM1 is a potent RAGE blocker, thereby controlling the progression of Aβ-mediated brain disorder [14]. Furthermore, metabolic syndrome is a risk factor for cognitive decline in AD, and RAGE has been associated with metabolic syndrome, as this receptor directly contributes to an inflammatory process and oxidative stress. Thus, the RAGE inhibition is able to reduce cellular toxicity, and therefore, RAGE inhibitors have therapeutic potential in retarding AD progression [15].
\nVitamin D (VD) acts through the vitamin D receptor (VDR), expressed in various tissues, including the nervous system. Vitamin D receptor is related to memory and cognitive functions. Research has reported a higher prevalence of VD deficiency in AD patients and individuals with VD deficiency had twice the risk of developing AD compared with individuals with sufficient VD concentrations. Several potential mechanisms which link low VD levels to the risk of dementia have been identified. First, VDR is expressed throughout the brain, including areas involved in memory, such as the hippocampus. The enzyme which synthesizes the active form of VD, 1α-hydroxylase, is also produced in various brain areas. Second, the VD active form (1,25dihydroxyvitamin D3 or 1,25-D3) regulates neurotrophin expression, such as neurotrophin 3, Glial cell-derived neurotrophic factor (GDNF) and neural growth factor (NGF). NGF has been implicated in maintaining and regulating the normal function of the septohippocampal pathway, which is involved in learning and memory. In addition, NGF levels are substantially reduced in AD patients and NGF negatively modulates APP protein gene expression, while increased APP expression is observed after NGF suppression. Furthermore, VD analogs increase APP binding to the NGF promoter, inducing NGF expression. Therefore, 1,25-D3 contributes to the development, survival, and function of neural cells [16].
\nThird, VD can stimulate macrophages, which increases amyloid plaque clearance. Fourth, the antioxidant effect of VD may be related to the modulation of antioxidant gene expression. Oxidative stress is known to contribute to the pathophysiology of neurodegenerative diseases, which leads to impaired cognitive and behavioral function. Genetic analyses of the human genome have pointed to several genes playing a role in susceptibility to AD, such as genes which are involved in inflammation and oxidative stress [7]. Fifth, VD also plays a role in vascular protection. Sixth, VD regulates neurotransmitter metabolism in the CNS, such as acetylcholine, dopamine, serotonin, and aminobutyric gamma acid. Finally, VD also reduces Aβ-induced cytotoxicity and apoptosis in primary cortical neurons. A recent study found that Aβ induction of nitric oxide synthase, part of the AD inflammatory process, depends on the VDR pathway disruption. VD supplementation improves age-related cognitive decline, learning, and memory in older rats. A cross-sectional study found that VD deficiency was associated with increased white matter volume and reduced gray matter volume. In summary, low VD concentrations may increase the risk of dementia and AD through vascular and neurodegenerative mechanisms [16].
\nVitamin D receptor interacts with the retinoid receptor X (RXR) to perform VD actions. Retinoid receptor X activation can stimulate the normal physiological processes by which APP is eliminated from the brain. Thus, RXR agonists may be useful in treating AD. Two-week treatment with an RXR agonist (bexarotene) in an AD animal model resulted in clearance of intraneuronal amyloid deposits. Additionally, treatment with bexarotene improved remote memory stabilization in fear-conditioned mice and improved olfactory habituation. In addition, bexarotene pretreatment improved neuronal survival in response to glutamate-induced excitotoxicity. The bexarotene effects were accompanied by reduced amyloid plaque levels, decreased astrogliosis and suppression of inflammatory gene expression. Therefore, treatment with RXR agonists can decrease neuron loss, reverse cognitive deficits, and improve neural circuit function in aggressive AD models [17]. Retinoid receptor X agonists can increase the expression of ApoE, ABCA1, and ABCG1 by activating RXR heterodimers. On the other hand, these beneficial effects are blocked by the RXR antagonist, which can accentuate cellular oxidative stress [18].
\nInterestingly, RXR decreased expression was identified in the AD mouse model and in cells treated with Aβ peptides [19]. However, the action mechanism of RXR ligands remains unknown, particularly in the context of human ApoE [20]. Retinoids have effects on various physiological and pathological processes in the brain. For example, retinoic acid (RA) signaling is widely detected in the adult CNS, including the amygdala, cortex, hypothalamus, hippocampus, and other brain areas. Retinoids are mainly involved in neural patterns, axon differentiation, and cell growth. Retinoids also play a key role in preserving the differentiated state of adult neurons. Impaired RA signaling may result in neurodegeneration and AD progression. Recent studies have shown severe deficiencies in mouse learning and memory during RA deprivation, indicating its importance in preserving memory. Defective cholinergic neurotransmission is related to cognitive deficits in AD. Retinoic acid is also known to increase choline acetyltransferase expression and the activity in neuronal cell lines. In addition, retinoids have been shown to inhibit the expression of proinflammatory chemokines and cytokines in microglia and astrocytes, which are activated in AD [21].
\nN-methyl-d-aspartate receptors (NMDAR) participate in CNS development and are involved in synaptic plasticity, which is essential for learning and memory. Cognitive symptoms associated with learning and memory deficits have been associated with glutaminergic neurotransmission disorders. Excitatory glutaminergic neurotransmission via NMDAR is critical for synaptic plasticity and neuron survival. However, excessive neuron stimulation by the glutamate neurotransmitter causes cytotoxicity and results in neuronal damage and death, underlying a potential mechanism of neurodegeneration in AD. Therefore, blocking NMDAR receptor-mediated glutaminergic neurotransmission can decrease cytotoxicity, thereby preventing further damage to neurons and cellular oxidative damage [22]. Therefore, NMDAR antagonists have emerged as potential compounds for AD patients since the receptor itself has many subunits and its variants have several brain functions. For example, conantokine acts as an NMDA receptor antagonist and plays an important role in understanding the importance of NMDA receptor inhibition in the AD treatment. Moreover, NMDAR activation might be blocked by an AD drug, memantine, an NMDAR antagonist which selectively blocks the function of extra synaptic NMDARs, but does not affect normal neurotransmission. However, memantine (and other current medications used to treat AD) only relieve the symptoms and do not alter the disease progression [23].
\nRegarding cholesterol receptors, some specific genotypes have been related to a higher or lower risk of dementia and AD. Even genotypes associated with AD neuropathology attenuation could be associated with late-onset of dementia. Liver nuclear X receptors (LXRs) are the main regulators of cholesterol homeostasis and CNS inflammation. The brain, which contains about 25% of total body cholesterol, requires a complex and balanced cholesterol metabolism to maintain neuronal function. Deregulation of cholesterol metabolism has been implicated in several neurodegenerative diseases, including AD. Due to their anti-inflammatory activities, LXRs play a crucial role in CNS function. Although LXR agonists have therapeutic potential in neurological diseases, the use of LXR in these pathologies remains problematic. The recent discovery of cholesterol derivatives which function as LXR agonists has shown new roles for LXRs in midbrain neurogenesis. Elucidating the repertoire of endogenous ligands for LXR will improve the understanding of how this receptor regulates CNS lipid metabolism [24].
\nNuclear X receptor signaling affects AD development through various pathways. Studies indicate that LXR genetic loss in transgenic mice results in increased amyloid plaques. Studies also suggest that LXRs activation in mice improves the expression of cholesterol efflux-linked genes (ApoE and ABCA-1), induces APP processing, and reduces Aß synthesis, with significant improvement in memory. Furthermore, LXR agonists have also been shown to inhibit neuroinflammation by modulating microglial phagocytosis and repressing COX2, MCP1, and INOS expression in glial cells [25]. The T allele of NR1H2 (rs2695121) presents the most significant risk for AD among all LXR-β gene polymorphisms. Taken together, these findings suggest that brain-penetrable LXR agonists or LXR modulators may be useful therapeutic agents for AD treatment and prevention [26].
\nAdditionally, chromosome 12p has been recognized as an AD-associated region. This chromosome includes genes for LDL receptor 1 (LRP1) and oxidized low-density lipoprotein receptor 1 (OLR1). OLR1 is a class E scavenger receptor and is a transmembrane glycoprotein. In vitro factors such as oxidized LDL, oxidative stress, and inflammatory cytokines, as well as in vivo factors such as diabetes mellitus, hyperlipidemia, and hypertension, may induce OLR1 expression. Increased oxidized LDL levels induce endothelial cell activation and dysfunction, apoptosis, and impaired vessel relaxation, thus contributing to atherosclerosis development and progression through OLR1. Epidemiological and clinical literature has reported an association between atherosclerosis, vascular risk factors, and AD. Therefore, ORL1 variations may lead to low efficiency in the oxidized LDL removal and therefore increased Aβ levels, which may result in neuronal death. Indeed, a single nucleotide polymorphism in OLR1 located in the 3′ untranslated region of the gene may influence regulatory microRNA binding and OLR1 homeostasis. Several studies have reported an association between this variant and AD [27].
\nToll-like receptors (TLRs) are innate immune system receptors which are activated by pathogens (PAMP) or damage-associated molecular patterns (DAMPs). Toll-like receptors are associated with neuronal injury in chronic inflammatory conditions but also with functional recovery after nerve injury. Amyloid aggregates seem to be a type of DAMP and may interact and activate standard recognition receptors. Two TLR actions (ligand binding and immune signaling) may have beneficial effects on AD pathology. Moreover, microglial activation represents an important AD hallmark. Analysis of genetic polymorphisms suggested relationships between TLR polymorphisms and AD risk, further supporting the hypothesis that TLRs are involved in AD [28]. In fact, TLR2 is elevated in the hippocampus and cortex of AD patients and mice. In this context, it was observed that a TLR2-binding peptide (WT TIDM) inhibited Aβ-induced microglial activation, reduced Aβ load, attenuated neuronal apoptosis, and improved memory and learning in mice. However, WT TIDM peptide was not effective in TLR2 knockout mice [29].
\nImportantly, TLR5 binds to APP with high-affinity, forming complexes which block APP toxicity. In turn, APP fibrils modulate the human TLR5 activation via flagellin, but APP cannot activate TLR5 signaling by themselves. Thus, TLR5-related biological data suggest this receptor as a potential agent in AD therapy [30]. A new TLR9 signaling pathway has recently been associated with the immune-inflammatory response, reducing Aβ levels in AD mice. Therefore, TLR9 may represent a functional candidate gene for AD [31]. Moreover, TLR4 has also been described in the brain and seems to regulate some physiological processes such as neurogenesis. In this sense, TLR4 plays an important role during neurodegenerative disorders. PRDX6 has been shown to inhibit neural stem cell neurogenesis by down-regulating the TLR4 signaling pathway [32]. An early TLR3-mediated signal improves Aβ neuronal autophagy, although it increases neuronal apoptosis in the late stage of AD. Similarly, TLR7, TLR8, and TLR9 may improve early Aβ microglial uptake, but over time, they contribute to neuroinflammation. Therefore, TLRs, in particular TLR2 and TLR4, represent suitable targets for therapeutic intervention in AD and carefully targeting them may increase Aβ autophagy and phagocytosis, as well as reduce inflammatory responses. Several modulators with selective TLR agonist or antagonist activity have been developed, and many of them could produce a therapeutic benefit in AD patients [33].
\nAnother molecule involved in AD is the chemokine receptor CX3C1 (CX3CR1), which performs IL-1β-dependent cognitive functions. It is known that CX3CR1 maintains microglial homeostasis and is essential for microglia function in synaptic support since it is highly expressed in microglia. In vivo, CX3CR1-GFP knock-in mice (in which GFP replaced a CX3CR1 allele) were used to study the role of microglia in AD and other brain diseases. Under physiological conditions, decreased CX3CR1 function affects cognitive functions in an IL-1β-dependent manner, as well as exacerbates LPS-induced inflammation, suggesting that CX3CR1 is essential for nerve synapses. In this context, CX3CL1/CX3CR1 axis dysregulation in AD may have neuroprotective and neurotoxic effects depending on the model used. It is also possible that CX3CR1 is involved in the death of neurons with intracellular TAU deposits and the subsequent TAU release [34]. Still, regarding chemokine receptors, CCL2 receptor (CCR2) was also associated with AD since CCR2 promotes the recruitment of bone marrow monocytes into the APP deposition sites in the parenchyma, where APP phagocytosis occurs. In mice, CCR2 deficiency accelerated early AD progression, impairing mononuclear phagocyte accumulation. CCR2−/− mice exhibited high APP levels and low CD11b+ cell recruitment in the brain. Importantly, these mice had increased mortality in a dose-dependent manner of the CCR2 gene. Subsequent studies showed that APP reduction is due to the monocyte accumulation in the perivascular spaces and possibly its infiltration into the brain parenchyma. These findings were corroborated by the fact that CCR2 deficiency worsened memory and increased soluble APP levels in mice [34].
\nThe main AD risk factor is aging, but there is growing evidence that chronic stress or stress-related disorders may increase the chance of developing AD. Thus, depressive disorder may be a risk factor for AD [35]. Stress promotes AD progression on neurons and glial cells, supporting an important pro-inflammatory role of glucocorticoid (GC) in the CNS [36]. Glucocorticoids act via two receptors: mineralocorticoid and glucocorticoid receptors (GR) and can participate in APP generation and APP activity in the brain. There is a cross-talk between APP and GRs in hippocampal excitatory synapses, which may contribute to abnormal brain activity during the AD pathogenesis. Both AD patients and AD mice have dysregulated hypothalamic-pituitary-adrenal (HPA) axis, marked by hypercortisolemia early in the AD pathology. Thus, in early AD, while APP levels slowly increase in the brain, GR activity is probably abnormally high [37]. Moreover, GRs hyperactivation induces brain changes similar to AD changes. In the brain, GCs are regulators of dendritic spine renewal and microglia activity, two strongly altered phenomena in AD. Although well established that GCs initiate the brain neuroinflammatory response, it is not known whether GRs modulate dendritic spine plasticity and microglial activity in AD [36].
\nSeveral strategies aiming GR has been tested to counteract HPA axis dysregulation and GC overproduction. Given the GR ubiquitous expression, antagonists have many side effects, limiting the GR therapeutic potential. However, a new class of selective molecules has been developed, acting as GR modulators. They selectively reduce GR-dependent pathogenic processes while retaining the beneficial aspects of GR signaling. Indeed, these “selective GR modulators” induce receptor conformations that allow the activation of only a subset of downstream signaling pathways, explaining their ability to combine agonistic and antagonistic properties. Therefore, targeting GR with selective modulators, alone or in association with current strategies, is attractive to develop new strategies aiming disorders associated with HPA axis dysregulation [35]. Dexamethasone, a GR agonist, was able to reduce the dendritic spine density, induced the microglia proliferation, and activated the microglia in the mouse hippocampus. Besides, in vitro microglial cells were activated by dexamethasone. In contrast, treatment with mifepristone, a GRs antagonist, strongly increased dendritic column density, decreased microglia density, and improved mice behavioral performance [36].
\nThere are a large number of polyunsaturated fatty acids in the nervous system, such as docosahexaenoic acid (DHA), an omega 3 carboxylic acid. The DHA binds to G-protein-coupled receptor 40 (GPR40) and exerts protective effects on the nervous system. For example, GPR40 can increase synaptic plasticity, neuronal activity, and inhibits neuronal apoptosis. In this context, GPR40 was considered a possible target in dementia [38]. The receptor is expressed in several brain areas, including the hippocampus, which is involved in learning and spatial memory. However, few studies are investigating the functional role of GPR40 in the brain [39]. One study evaluated the GPR40 functional role in the AD mouse model. Groups treated with GPR40 significantly improved cognitive performance and GPR40 agonist-treated groups improved learning and memory skills in various tests. Besides, GPR40 activation caused CREB phosphorylation and increased neurotrophic factors levels, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) in hippocampal neurons. These results suggest that GPR40 can be a therapeutic candidate for neurogenesis and neuroprotection in AD treatment and prevention [39] since GPR40 agonists can promote adult neurogenesis, inhibit neuronal apoptosis, and play a vital role in protecting nerves and decreasing brain damage [38].
\nThe triggered receptor expressed in myeloid cells 2 (TREM2) is a soluble protein carried by macrophages through ventricles and choroid plexus, entering the brain parenchyma through radial glial cells. TREM2 is important for innate immunity, but it is also essential for neuroplasticity and myelination. During later stages of life, the TREM2 absence can accelerate aging processes, neuronal cell loss and reduce microglial activity, leading to neuroinflammation. Inflammation plays an important role in neurodegenerative diseases and TREM2 can be important to immunomodulation and neuroprotection [40]. As a member of the immunoglobulin superfamily, TREM2 can suppress inflammatory responses, mediates phagocytic pathways, is involved with neuronal survival and neurogenesis, as well as contributes to CNS neuroimmune homeostasis. Changes in TREM2 are involved in AD-related neuropathology, including Aβ deposition, tau hyperphosphorylation, neuroinflammation, and neuronal and synaptic losses in AD animal models. However, the precise underlying mechanisms about TREM2 have not yet been fully characterized [41]. Besides, TREM2 might be related to microglial activation, promoting the association of microglial cells with APP plaques. Therefore, microglia can decrease APP plaque growth, limiting APP toxicity. On the other hand, this phagocytotic capacity is impaired by TREM2 deficiency. Moreover, different mutations in TREM2 are associated with AD [42, 43]. Interestingly, recent findings also suggested that the association between TREM2 variants and the AD risk varies according to different ethnicities and populations [41].
\nThe serotoninergic neurotransmitter system has been implicated in AD pathogenesis. The 5-hydroxytryptamine 6 receptor (5HTR6) is expressed in brain areas involved with cognitive processes and has been investigated as a possible therapeutic target in AD symptomatology. Besides, 5HTR6 may be added to currently approved “Food and Drug Administration” therapies: cholinesterase inhibitors and NMDA receptor antagonists since 5HTR6 controls the pyramidal neurons’ migration during corticogenesis. In addition, 5HTR6 is a TOR signaling activator and seems to regulate GABAergic, glutamatergic, and cholinergic activity. Therefore, 5HTR6 is involved in cognition, anxiety, memory, affective state, among others [44]. Several kinds of research have been conducted with selective 5HTR6 antagonists. These antagonists act by modulating the glutamate and GABA levels, consequently increasing dopamine, ACh, and norepinephrine concentrations in the brain, all compromised in AD. Besides, 5HTR6 agonists have also been shown to have pro-cognitive effects. Partial or inverse agonists may produce promising cognitive effects [44, 45]. Moreover, 5HTR6 gene variants can be a genetic risk factor for late-onset AD and 5HTR6 polymorphisms are possibly involved with AD susceptibility, such as the C267T polymorphism [44]. However, there are relatively few genetic studies investigating the association between AD and gene variants involved in the serotonergic system.
\nEvidence regarding the involvement of the endocannabinoid system (ECS) in the AD pathogenesis raised questions about the development of new therapeutic approaches for AD based on endocannabinoid regulation. The endocannabinoid system is composed of receptors, endogenous ligands, and enzymes, which are involved in AD pathogenesis [46]. Endocannabinoid system-directed drugs can exert beneficial effects on mood, as well as modulate neuroinflammation, synaptic plasticity, neurotoxicity, apoptosis, cell proliferation, cell differentiation, and oxidative stress [47, 48]. Moreover, cannabis tetrahydrocannabinol (THC) induces neurogenesis, removes Aβ peptides, and decreases neurofibrillary tangles. The hippocampus and microglia, key actors in dementia pathophysiology, express 1 and 2 cannabinoid receptors, respectively [49]. Type 2 cannabinoid receptor (CNR2) is overexpressed in activated microglia in different areas of the nervous system. Activated CNR2 has the potential to disrupt the AD process and treat the symptoms, reducing neurodegeneration, neuroinflammation, and improving spatial memory [50]. The role of the type 1 cannabinoid receptor (CNR1) is unclear. However, CNR1 can up-regulate anti-apoptotic proteins in rats [49].
\nPeroxisome proliferator-activated γ receptor (PPARγ) regulates the transcription of several genes involved in inflammation, immune response, insulin sensitivity, and lipid metabolism. The pathways governed by PPARγ overlap the biological pathways implicated in AD pathogenesis according to various pieces of evidence. Besides, PPARγ regulates the expression of seven AD-associated genes, including ApoE, ABCA1, and ABCG1. Increasing ApoE lipid levels facilitate soluble Aβ degradation. Studies using AD animal models have suggested that PPARγ exerts direct and indirect effects on APP protein metabolism [51]. Peroxisome proliferator-activated γ receptor is up-regulated in AD due to existing neuroinflammation and PPARγ agonists can be used in AD and shows anti-inflammatory effects, as well as improve learning and memory. Thus, PPARγ might be a significant new therapeutic target in AD treatment [52]. In addition, emerging evidence suggests that PPARγ effectively regulates microglia activation under physiological and pathological conditions, facilitating Aβ microglial phagocytosis [53]. In addition, PPARγ polymorphisms have been studied in AD; however, the results are controversial and inconclusive [54].
\nThe NOD-like receptor pyrin domain-containing-3 (NLRP3) is the best known member of the NLR family. Importantly, APP can activate the NLRP3 inflammasome and increase NLRP3, caspase1, and IL1-β genes expression [55]. In microglia, NLRP3 activation is essential for interleukin-1β (IL1-β) maturation and subsequent inflammatory events. Besides, NLRP3 is possibly involved in AD pathogenesis through oxidative stress [56]. One study showed that NLRP3 knock-out mice were largely protected from spatial memory loss and other AD-associated sequelae, showing reduced caspase-1 and IL1-β activation, as well as increased Aβ clearance. Microglial activation by Aβ can initiate innate immune responses in CNS via NLRP3, even before the Aβ deposition. These results show an important role of the NLRP3 axis in the AD pathogenesis and suggest that NLRP3 inflammasome inhibition might be a new therapeutic intervention for the disease [57]. Non-steroidal anti-inflammatory drugs can inhibit NLRP3 inflammasome via reversible blockade of volume-regulated anionic channels in the plasma membrane, inhibiting cognitive impairment in AD mice models [58]. The loss of NLRP3 inflammasome function also reduced tau hyperphosphorylation and aggregation (involved in AD pathogenesis) by regulating tau kinases and phosphatases. Tau, in turn, activated the NLRP3 inflammasome. The intracerebral injection containing Aβ induced tau pathology in an NLRP3-dependent manner. Therefore, these data suggest an important role of NLRP3, microglia, and inflammasome activation in AD tauopathies [59]. Finally, virgin coconut oil improved hippocampal health, memory, and learning in AD mice models by inhibiting NLRP3 and reducing oxidative stress [55].
\nNuclear receptors family and G-protein-coupled receptors are probably the receptors families most involved with AD (Table 1). Additionally, the cerebral cortex is the main area where most of the receptors involved in AD express themselves. The cerebral cortex’s physical area, its complexity, and its involvement with several relevant functions in AD probably justify this fact. Despite the small size of the hippocampus, this region is significantly affected in AD. While the cerebral cortex is mainly involved in decision making, subjective thinking, consequences of action assessment, perception, and attention, the hippocampus is mainly related to memory. As a key component of cortico-hippocampal networks, the perirenal cortex plays an important role in memory processes, especially familiarity-based recognition memory. Therefore, disrupted functional connectivity of this cortical region as a result of early neurodegeneration may contribute to altered brain rhythms and cognitive failures observed in the early clinical phase of AD patients [11].
\nReceptor/family | \nMain expression area in human CNS | \nMain roles in AD | \n
---|---|---|
Acetylcholine receptors (AChR) Nicotinic Receptors | \nCerebral cortex and cerebellum | \nInteracts with APP protein and exert positive effects on memory and attention [1, 2]. | \n
Estrogen receptors (ER) Nuclear receptor family | \nBasal ganglia and hippocampus | \nIncreases neural plasticity and neurogenesis, affecting cognitive functions and the brain regenerative potential. May play beneficial effects in reducing the brain inflammatory process [4, 5, 6]. | \n
Ryanodine receptor 3 (RyR3) Calcium channels | \nBasal ganglia | \nPlays negative effects related to synaptic transmission and synaptic plasticity. Associated with memory loss and age-related cognition decline [7, 8, 9]. | \n
Gamma-Aminobutyric Acid receptor (GABAR) Ionotropic receptor | \nCerebral cortex | \nRegulates learning, memory, cognitive function, controls the glutamate release, and reduces APP toxicity [10, 11, 12]. | \n
Receptor for advanced glycation end products (RAGE) Immunoglobulins superfamily | \nCerebellum | \nContributes to neuronal death and inflammation and is involved with the APP transport, oxidative stress, and cerebral blood flow [14, 15]. | \n
Vitamina D receptor (VDR) Nuclear receptor family | \nCerebral cortex and hippocampus | \nInteracts with SMAD3, regulating APP transcription through TGFβ signaling. Suppress APP gene promoter activity [16]. | \n
Retinoid X receptor (RXR) Nuclear receptor family | \nCerebral cortex | \nStimulates physiological mechanisms of APP elimination, decreasing APP-induced deficits [17, 18, 21]. | \n
N-methyl-D-aspartate receptors (NMDAR) Ionotropic receptor | \nCerebral cortex and hypothalamus | \nParticipates in CNS development and is involved in synaptic plasticity, essential for learning and memory [22, 23]. | \n
Liver X receptor β (LXR) Nuclear receptor family | \nCerebral cortex | \nRegulates the cholesterol homeostasis and inflammation in CNS. May play roles in neurogenesis, APP processing, and microglial phagocytosis modulation [24, 25, 26]. | \n
Low-density lipoprotein receptor (LDLR) Lipoprotein receptor family | \nPons and medulla | \nMediates the increase in ApoE expression induced by APP protein [27]. | \n
Oxidized low-density lipoprotein receptor 1 (OLR1) Lipoprotein receptor family | \nMidbrain | \nMediates the uptake and internalization of low-density oxidized lipoprotein (oxLDL), which may be involved in AD [27]. | \n
Toll-like receptor 4 (TLR4) Toll-like receptor family | \nHippocampus | \nInduces CREB signaling, which regulates neuron survival, neuronal gene expression, and neurogenesis in the adult subventricular zone [28, 32, 33]. | \n
Toll-like receptor 5 (TLR5) Toll-like receptor family | \nThalamus | \nBinds to APP oligomers and fibrils, forming complexes that block APP toxicity [28, 30, 31]. | \n
C-C chemokine receptor type 2 (CCR2) Chemokine receptor family | \nPons and medulla | \nPromotes monocyte recruitment to APP deposition sites, where these cells can phagocyte APP proteins [34]. | \n
Chemokine receptor CX3C 1 (CX3CR1) Chemokine receptor family | \nMidbrain, pons, and medulla | \nMaintains microglial function in synaptic support and performs IL-1β dependent cognitive functions [34]. | \n
Glucocorticoid receptor (GCRs) Glucocorticoid receptor family | \nCerebellum | \nParticipates in the generation and activity of APP protein in the brain [36, 37]. | \n
G-protein-coupled receptor 40 (GPR40) G-protein-coupled receptor family | \nSpinal cord | \nPromotes neurogenesis, inhibits neuronal apoptosis, and plays a role in protecting nerves and decreasing brain damage [38, 39]. | \n
Triggered receptor expressed on myeloid cells 2 (TREM-2) Immunoglobulins superfamily | \nMidbrain | \nParticipates in microglial survival, inflammatory response, phagocytosis, dendritic cell maturation and others [40, 41, 42, 43]. | \n
5-hydroxytryptamine 6 receptor (5 HTR6) G-protein-coupled receptor family | \nBasal ganglia | \nControls the pyramidal neurons migration during corticogenesis, activates TOR signaling, and regulates the GABAergic, glutamatergic, and cholinergic activity. Involved in cognition, anxiety, memory, mood, among others [44, 45]. | \n
Cannabinoid receptor (CNR) G-protein-coupled receptor family | \nCerebral cortex | \nDisrupt the AD process, reduce symptoms, neurodegeneration, neuroinflammation, and improve spatial memory [47, 48, 49, 50]. | \n
Peroxisome proliferator-activated γ receptor (PPARγ) Nuclear receptor family | \nAmygdala | \nParticipates in pathways involved with lipid metabolism and immune response implicated in AD etiology. PPARγ acts as a transcriptional regulator of several genes involved in AD pathogenesis [51, 52, 53]. | \n
NOD-like receptor pyrin domain-containing-3 (NLRP3) NOD-like receptor family | \nPons and medulla | \nThe NLRP3 activation leads to IL-1β and IL-18 production that play a role in the inflammatory response and oxidative stress in AD pathogenesis. [56, 57, 58, 59]. | \n
Sigma-1 receptor (σ1R) Chaperone protein | \nCerebral cortex | \nInhibits enzymes involved in AD, such as acetylcholinesterase, 5-lipoxygenase, and monoamine oxidase. Protects neurons against oxidative stress, contributing to neuronal tissues repair [64]. | \n
Calcium sensing receptor (CaSR) G-protein-coupled receptor family | \nCerebral cortex and hippocampus | \nRole in hippocampal neurons degeneration. APP is able to increase intracellular calcium by opening calcium-permeable cationic channels in hippocampal neurons [65]. | \n
Alzheimer’s disease associated receptors.
Although few receptors involved with AD are expressed in the hypothalamus and amygdala (when compared to the expression in the cortex, hippocampus, pons, medulla, and basal ganglia), it is known that AD is closely associated with changes in mood and motivation. However, these associations depend on the AD stage. Most of the receptors involved with AD are expressed in more than one nervous system area, showing the involvement of several brain regions in AD. Additionally, microglia is one of the main cell types in which AD-associated receptors express themselves, highlighting the relevance of microglia in AD, especially in the removal of toxic peptides. Additionally, AD-associated receptors are involved with several metabolic pathways, which may be directly or indirectly related to the disease. The APP elimination or the blockage of pathways related to the APP synthesis is the main function performed by the receptors involved with AD (Table 1, Figure 1). Besides, many receptors are directly involved with cognitive, memory, and/or learning functions and many receptors are associated with more than one AD-related function (Table 1, Figure 1). Finally, AD-associated receptors are also related to nervous system plasticity, including neuronal and microglial survival, nervous system development (positive plasticity), and neuronal death (negative plasticity). This suggests that these receptors participate in several long-term changes in the nervous system (long-term plasticity) [60].
\nProteins associated with AD. Proteins related to AD are shown according to their protective (a) or pathological (b) effects in AD. The receptors located in the green boxes are associated with neuroprotective effects on AD. Receptors located in red boxes are associated with AD pathophysiology. Proteins are shown according to their location in the cell (nucleus, membrane, intracellular or extracellular). Arrows/triangles represent activation, induction or increase. Inverted bars/triangles represent inhibition, deficit or decrease. Protein associated to AD protection are related to proteins involved in AD pathophysiological process. Two triangles represent overactivation. Elements in the figure are not showed in real scale. ROS, reactive oxygen.
Finally, most of the receptors involved in AD (67%) are associated with beneficial effects on the disease. These receptors include nuclear receptors, such as VDR, membrane receptors, such as TLR5, and cytoplasmic receptors, such as GABAR. Most of the AD-associated receptors are found in the membrane of nerve cells (61%). Among the neuroprotective receptors, we can highlight the vitamin D receptor, responsible for vitamin D actions. Vitamin D is increasingly recognized as a substance involved in neuronal survival, taking part in psychiatric and neurodegenerative diseases such as AD. The participation of vitamin D in neuronal survival may be related to its role in inhibiting the cellular oxidative stress and APP synthesis. Therefore, supplementation with vitamin D can help in the current AD treatment [61]. A beneficial role in inflammation, played by some receptors acting on inflammatory pathways, such as TLRs, has also been shown to be beneficial in the AD treatment [62]. More and more new treatments are being researched for AD, but unfortunately, the improvements have not been significant. What has been sought are combinations of treatments, which can result in some side effects in the elderly patient. Besides, current treatments are only symptomatic, that is, they do not modify the AD stage. These are cholinesterase inhibitors, used in all AD stages as they result in some beneficial effects on cognition and behavior. However, therapies affecting the AD stage are still under development. Therefore, efficient research must be conducted in this direction, instead of alleviating only the symptoms. Immunotherapy, for example, can be a viable option soon [63].
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr.",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Rheinmetall (Germany)",country:{name:"Germany"}}},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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A new type of memristors with a floating photogate based on biocompatible graphene and other 2D crystals with extremely low power consumption and footprint is considered. The photocatalytic oxidation of graphene is proposed as an effective method of creating synapse-like 2D memristive devices with photoresistive switching for nonvolatile electronic memory of ultrahigh density. 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This chapter will discuss the state-of-the-art research trend on neuromorphic computing with memristors as electronic synapses. Furthermore, a novel three-dimensional (3D) neuromorphic computing architecture combining memristor and monolithic 3D integration technology would be introduced; such computing architecture has capabilities to reduce the system power consumption, provide high connectivity, resolve the routing congestion issues, and offer the massively parallel data processing. 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As an initial model equation, an integrodifferential equation of Voltaire type was introduced, which was reduced by means of a special choice of difference kernels to a differential equation with nonlocal derivatives of fractional-order variables. An explicit finite-difference scheme is proposed, and questions of its stability and convergence are investigated. A computer study of the proposed numerical algorithm on various test examples of the hereditary oscillators Airy, Duffing, and others was carried out. 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He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. 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His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. 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He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. 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He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. 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She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. 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Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\r\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\r\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Orthodontist, Assoc Prof in the Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"344229",title:"Dr.",name:"Sankeshan",middleName:null,surname:"Padayachee",slug:"sankeshan-padayachee",fullName:"Sankeshan Padayachee",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"315727",title:"Ms.",name:"Kelebogile A.",middleName:null,surname:"Mothupi",slug:"kelebogile-a.-mothupi",fullName:"Kelebogile A. Mothupi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"337613",title:"Mrs.",name:"Tshakane",middleName:null,surname:"R.M.D. Ralephenya",slug:"tshakane-r.m.d.-ralephenya",fullName:"Tshakane R.M.D. Ralephenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}}]}},subseries:{item:{id:"14",type:"subseries",title:"Cell and Molecular Biology",keywords:"Omics (Transcriptomics; Proteomics; Metabolomics), Molecular Biology, Cell Biology, Signal Transduction and Regulation, Cell Growth and Differentiation, Apoptosis, Necroptosis, Ferroptosis, Autophagy, Cell Cycle, Macromolecules and Complexes, Gene Expression",scope:"The Cell and Molecular Biology topic within the IntechOpen Biochemistry Series aims to rapidly publish contributions on all aspects of cell and molecular biology, including aspects related to biochemical and genetic research (not only in humans but all living beings). We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics include, but are not limited to: Advanced techniques of cellular and molecular biology (Molecular methodologies, imaging techniques, and bioinformatics); Biological activities at the molecular level; Biological processes of cell functions, cell division, senescence, maintenance, and cell death; Biomolecules interactions; Cancer; Cell biology; Chemical biology; Computational biology; Cytochemistry; Developmental biology; Disease mechanisms and therapeutics; DNA, and RNA metabolism; Gene functions, genetics, and genomics; Genetics; Immunology; Medical microbiology; Molecular biology; Molecular genetics; Molecular processes of cell and organelle dynamics; Neuroscience; Protein biosynthesis, degradation, and functions; Regulation of molecular interactions in a cell; Signalling networks and system biology; Structural biology; Virology and microbiology.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11410,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,series:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983"},editorialBoard:[{id:"79367",title:"Dr.",name:"Ana Isabel",middleName:null,surname:"Flores",slug:"ana-isabel-flores",fullName:"Ana Isabel Flores",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRpIOQA0/Profile_Picture_1632418099564",institutionString:null,institution:{name:"Hospital Universitario 12 De Octubre",institutionURL:null,country:{name:"Spain"}}},{id:"328234",title:"Ph.D.",name:"Christian",middleName:null,surname:"Palavecino",slug:"christian-palavecino",fullName:"Christian Palavecino",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000030DhEhQAK/Profile_Picture_1628835318625",institutionString:null,institution:{name:"Central University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",slug:"francisco-javier-martin-romero",fullName:"Francisco Javier Martin-Romero",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",institutionString:null,institution:{name:"University of Extremadura",institutionURL:null,country:{name:"Spain"}}}]},onlineFirstChapters:{paginationCount:17,paginationItems:[{id:"82751",title:"Mitochondria-Endoplasmic Reticulum Interaction in Central Neurons",doi:"10.5772/intechopen.105738",signatures:"Liliya Kushnireva and Eduard Korkotian",slug:"mitochondria-endoplasmic-reticulum-interaction-in-central-neurons",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"82716",title:"Advanced glycation end product induced endothelial dysfunction through ER stress: Unravelling the role of Paraoxonase 2",doi:"10.5772/intechopen.106018",signatures:"Ramya Ravi and Bharathidevi Subramaniam Rajesh",slug:"advanced-glycation-end-product-induced-endothelial-dysfunction-through-er-stress-unravelling-the-rol",totalDownloads:13,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"82195",title:"Endoplasmic Reticulum: A Hub in Lipid Homeostasis",doi:"10.5772/intechopen.105450",signatures:"Raúl Ventura and María Isabel Hernández-Alvarez",slug:"endoplasmic-reticulum-a-hub-in-lipid-homeostasis",totalDownloads:17,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"82103",title:"The Role of Endoplasmic Reticulum Stress and Its Regulation in the Progression of Neurological and Infectious Diseases",doi:"10.5772/intechopen.105543",signatures:"Mary Dover, Michael Kishek, Miranda Eddins, Naneeta Desar, Ketema Paul and Milan Fiala",slug:"the-role-of-endoplasmic-reticulum-stress-and-its-regulation-in-the-progression-of-neurological-and-i",totalDownloads:15,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"80954",title:"Ion Channels and Neurodegenerative Disease Aging Related",doi:"10.5772/intechopen.103074",signatures:"Marika Cordaro, Salvatore Cuzzocrea and Rosanna Di Paola",slug:"ion-channels-and-neurodegenerative-disease-aging-related",totalDownloads:12,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Ion Channels - From Basic Properties to Medical Treatment",coverURL:"https://cdn.intechopen.com/books/images_new/10838.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"81647",title:"Diabetes and Epigenetics",doi:"10.5772/intechopen.104653",signatures:"Rasha A. 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