Cholinergic Hypothesis Research Articles

The effects of hesperidin on sodium arsenite-induced different organ toxicity in rats on metabolic enzymes as antidiabetic and anticholinergics potentials: A biochemical approach.

In our work, it was purposed to investigate the effects of sodium arsenite (SA) and hesperidin (HSP) administered to rats on some metabolic enzymes including carbonic anhydrase (CA), aldose reductase (AR), paraoxonase-1 (PON1), α-glycosidase (α-Gly), butyrylcholine esterase (BChE), acetylcholine esterase (AChE) enzymes activities in the brain, heart, liver, testis, and kidney tissues of rats. CA activities were significantly decreased in testis, liver, and heart tissues of rats given HSP, SA, SA+HSP-100, and SA+HSP-200 compared to control (p<0.05). In liver tissue, AChE and BChE enzymes activities were significantly reduced given in all groups. In all tissues, α-Gly activity was reduced given in all groups. In the current study, aldose reductase enzyme activity was reduced significantly in testis, brain, and heart tissues of all groups compared to standard (p<0.05). PON1 enzyme activity was increased significantly in kidney and liver tissues of rats HSP groups and decreased SA groups compared to control. PRACTICAL APPLICATIONS: α-Glycosidase is the key enzyme involved in the digestion of the carbohydrate. Another enzyme α-amylase hydrolyzes the α-linked polysaccharide derivatives into oligosaccharide molecules, and α-glycosidase enzymes, which are characterized in small intestine, catalyze the final stage in the digestive mechanism of carbohydrate molecule to release absorbable monosaccharides like glucose. Conforming to the cholinergic hypothesis, impairment of the cholinergic pathways plays a good role in the development of neurodegenerative diseases like depression, schizophrenia, Alzheimer's disease (AD) problems with the regulation of traumatic brain injury and sleep. The AD is the main reason for dementia disease, and mild to moderate cases are generally treated with AChE inhibitors. Human CA inhibitor compounds are clinically used for more than 70 years as antiglaucoma and diuretics drugs.

The Role of Cholinergic Midbrain Neurons in Startle and Prepulse Inhibition.

One of the two major cholinergic centers of the mammalian brain is located in the midbrain, i.e., the pedunculopontine tegmentum (PPTg) and the adjacent laterodorsal tegmentum. These cholinergic neurons have been shown to be important for e.g., arousal, reward associations, and sleep. They also have been suggested to mediate sensorimotor gating, measured as prepulse inhibition of startle (PPI). PPI disruptions are a hallmark of schizophrenia and are observed in various other psychiatric disorders, where they are associated with, and often predictive of, other cognitive symptoms. PPI has been proposed to be mediated by a short midbrain circuitry including inhibitory cholinergic projections from PPTg to the startle pathway. Although the data indicating the involvement of the PPTg is very robust, some more recent evidence challenges that there is a cholinergic contribution to PPI. We here use transient optogenetic activation of specifically the cholinergic PPTg neurons in male and female rats to address their role in startle modulation in general, and in PPI specifically. Although we could confirm the crucial role of PPTg cholinergic neurons in associative reward learning, validating our experimental approach, we found that activation of cholinergic PPTg neurons did not inhibit startle responses. In contrast, activation of cholinergic PPTg neurons enhanced startle, which is in accordance with their general role in arousal and indicate a potential involvement in sensitization of startle. We conclude that noncholinergic PPTg neurons mediate PPI in contrast to the longstanding hypothetical view that PPI is mediated by cholinergic PPTg neurons.SIGNIFICANCE STATEMENT Activation of cholinergic neurons in the midbrain has been assumed to mediate prepulse inhibition of startle (PPI), a common measure of sensorimotor gating that is disrupted in schizophrenia and other psychiatric disorders. We here revisit this long-standing hypothesis using optogenetic activation of these specific neurons combined with startle testing in rats. In contrast to the hypothetical role of these neurons in startle modulation, we show that their activation leads to an increase of baseline startle and to prepulse facilitation. This supports recent data by others that have started to cast some doubt on the cholinergic hypothesis of PPI, and calls for a revision of the theoretical construct of PPI mechanisms.

The cholinergic system in the pathophysiology and treatment of Alzheimer's disease.

Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-β proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.

Fucosterol inhibits the cholinesterase activities and reduces the release of pro-inflammatory mediators in lipopolysaccharide and amyloid-induced microglial cells

According to the cholinergic hypothesis, memory impairment in patients with Alzheimer’s disease (AD) is associated with the deficit of cholinergic function in the brain. In addition, microglial activation plays an important role in AD by producing pro-inflammatory cytokines, nitric oxide (NO), and prostaglandin E2 (PGE2). It was noted that lipopolysaccharide (LPS) and β-amyloid (Aβ) induced microglial activation leading to neuroinflammation and ultimately neuronal cell death. Fucosterol, a plant sterol found in brown algae, has been reported to exhibit several bioactivities. This study aimed to investigate the anti-cholinesterase activities of fucosterol and its effects on the release of pro-inflammatory mediators by LPS- and Aβ-induced microglial cells. Cholinesterase inhibition was determined using the modified Ellman colorimetric method. Expression of pro-inflammatory mediators was determined using RT-PCR and ELISA. The NO content was determined using the Griess test. Fucosterol exhibited dose-dependent inhibitory activities against both acetylcholinesterase and butyrylcholinesterase. It significantly inhibited the production of cytokines, namely interleukins (IL-6, IL-1β), tumor necrosis factor-α (TNF-α), NO, and PGE2 in LPS- or Aβ-induced microglial cells. Fucosterol provided protective effects against Aβ-mediated neuroinflammation by inhibiting the production of pro-inflammatory mediators. These findings provided insights into the development of fucosterol as a potential drug candidate for AD, a multifactorial neurodegenerative disorder.

Combined QSAR, molecular docking and molecular dynamics study on new Acetylcholinesterase and Butyrylcholinesterase inhibitors

Background and purposeThis work deals with several molecular modeling methods used to discover new therapeutic agents for treating the Alzheimer’s disease (AD). The cholinergic hypothesis was initially presented over 30 years ago and suggests that a dysfunction of acetylcholine containing neurons in the brain. Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE) are of the keys targets of drugs for treating AD. MethodsQSAR, Molecular Docking/Dynamics and ADME properties were carried out in order to study 36 compounds that belong to the 4-[(diethylamino)methyl]-phenol derivatives and test their AChE and BuChE inhibitory activities, MOE, HyperChem and others softwares were used to find the best compounds with high affinity. ResultsThe QSAR models exhibited good statistical values for both targets AChE (R2adj = 0.660, q2 = 0.70, F-ratio = 18.008) and BuChE (R2adj = 0.726, q2 = 0.75, F-ratio = 31.864). The interactions between the studied inhibitors and our targets were further explored through molecular docking and molecular dynamics simulations. A few key residues (TRP279, TYR334, PHE330 and TRP84) at the binding site of AChE and key residues (HIS438, TYR332, PHE329 and TRP82) at the binding site of BuChE were identified. ConclusionBased on this study compounds 23 and 28 have no violated Lipinski’s rule of five and thus, showing the possibility of being potential candidates for further studies in drug development process against the AChE and BuChE targets respectively.

Expression of a Constitutively Active Human Insulin Receptor in Hippocampal Neurons Does Not Alter VGCC Currents.

Memory and cognitive decline are the product of numerous physiological changes within the aging brain. Multiple theories have focused on the oxidative, calcium, cholinergic, vascular, and inflammation hypotheses of brain aging, with recent evidence suggesting that reductions in insulin signaling may also contribute. Specifically, a reduction in insulin receptor density and mRNA levels has been implicated, however, overcoming these changes remains a challenge. While increasing insulin receptor occupation has been successful in offsetting cognitive decline, alternative molecular approaches should be considered as they could bypass the need for brain insulin delivery. Moreover, this approach may be favorable to test the impact of continued insulin receptor signaling on neuronal function. Here we used hippocampal cultures infected with lentivirus with or without IRβ, a constitutively active, truncated form of the human insulin receptor, to characterize the impact continued insulin receptor signaling on voltage-gated calcium channels. Infected cultures were harvested between DIV 13 and 17 (48h after infection) for Western blot analysis on pAKT and AKT. These results were complemented with whole-cell patch-clamp recordings of individual pyramidal neurons starting 96h post-infection. Results indicate that while a significant increase in neuronal pAKT/AKT ratio was seen at the time point tested, effects on voltage-gated calcium channels were not detected. These results suggest that there is a significant difference between constitutively active insulin receptors and the actions of insulin on an intact receptor, highlighting potential alternate mechanisms of neuronal insulin resistance and mode of activation.

Recent advances in cholinergic imaging and cognitive decline-Revisiting the cholinergic hypothesis of dementia.

Although the cholinergic hypothesis of dementia provided a successful paradigm for the development of new drugs for dementia, this hypothesis has waned in popularity. Cholinergic brain imaging may provide novel insights into the viability of this hypothesis. Cholinergic receptor and forebrain volumetric studies suggest an important role of the cholinergic system in maintaining brain network integrity that may deteriorate with cognitive decline in Alzheimer disease (AD) and Lewy body disorders (LBD). Bidirectional changes in regional receptor expression may suggest the presence of compensatory responses to neurodegenerative injury. Cholinergic system changes are more complex in LBD because of additional subcortical degenerations compared to AD. Cholinergic-dopaminergic interactions affect attentional, verbal learning and executive functions, and impairments in these two transmitter systems may jointly increase the risk of dementia in Parkinson disease. The cholinergic hypothesis is evolving from a primary focus on memory toward expanded cognitive functions modulated by regionally more complex and interactive brain networks. Cholinergic network adaptation may serve as a novel research target in neurodegeneration.

Evaluation of Metabolic and Synaptic Dysfunction Hypotheses of Alzheimer's Disease (AD): A Meta-Analysis of CSF Markers.

Background:Alzheimer’s disease (AD) is currently incurable and a majority of investigational drugs have failed clinical trials. One explanation for this failure may be the invalidity of hypotheses focus-ing on amyloid to explain AD pathogenesis. Recently, hypotheses which are centered on synaptic and met-abolic dysfunction are increasingly implicated in AD.Objective:Evaluate AD hypotheses by comparing neurotransmitter and metabolite marker concentrations in normal versus AD CSF.Methods:Meta-analysis allows for statistical comparison of pooled, existing cerebrospinal fluid (CSF) marker data extracted from multiple publications, to obtain a more reliable estimate of concentrations. This method also provides a unique opportunity to rapidly validate AD hypotheses using the resulting CSF con-centration data. Hubmed, Pubmed and Google Scholar were comprehensively searched for published Eng-lish articles, without date restrictions, for the keywords “AD”, “CSF”, and “human” plus markers selected for synaptic and metabolic pathways. Synaptic markers were acetylcholine, gamma-aminobutyric acid (GABA), glutamine, and glycine. Metabolic markers were glutathione, glucose, lactate, pyruvate, and 8 other amino acids. Only studies that measured markers in AD and controls (Ctl), provided means, standard er-rors/deviation, and subject numbers were included. Data were extracted by six authors and reviewed by two others for accuracy. Data were pooled using ratio of means (RoM of AD/Ctl) and random effects meta-analysis using Cochrane Collaboration’s Review Manager software.Results:Of the 435 identified publications, after exclusion and removal of duplicates, 35 articles were in-cluded comprising a total of 605 AD patients and 585 controls. The following markers of synaptic and met-abolic pathways were significantly changed in AD/controls: acetylcholine (RoM 0.36, 95% CI 0.24-0.53, p<0.00001), GABA (0.74, 0.58-0.94, p<0.01), pyruvate (0.48, 0.24-0.94, p=0.03), glutathione (1.11, 1.01-1.21, p=0.03), alanine (1.10, 0.98-1.23, p=0.09), and lower levels of significance for lactate (1.2, 1.00-1.47, p=0.05). Of note, CSF glucose and glutamate levels in AD were not significantly different than that of the controls.Conclusion:This study provides proof of concept for the use of meta-analysis validation of AD hypothe-ses, specifically via robust evidence for the cholinergic hypothesis of AD. Our data disagree with the other synaptic hypotheses of glutamate excitotoxicity and GABAergic resistance to neurodegeneration, given ob-served unchanged glutamate levels and decreased GABA levels. With regards to metabolic hypotheses, the data supported upregulation of anaerobic glycolysis, pentose phosphate pathway (glutathione), and anaple-rosis of the tricarboxylic acid cycle using glutamate. Future applications of meta-analysis indicate the pos-sibility of further in silico evaluation and generation of novel hypotheses in the AD field.

Synthesis, pharmacology and molecular docking on multifunctional tacrine-ferulic acid hybrids as cholinesterase inhibitors against Alzheimer’s disease

The cholinergic hypothesis has long been a “polar star” in drug discovery for Alzheimer’s disease (AD), resulting in many small molecules and biological drug candidates. Most of the drugs marketed for AD are cholinergic. Herein, we report our efforts in the discovery of cholinesterases inhibitors (ChEIs) as multi-target-directed ligands. A series of tacrine-ferulic acid hybrids have been designed and synthesised. All these compounds showed potent acetyl-(AChE) and butyryl cholinesterase(BuChE) inhibition. Among them, the optimal compound 10g, was the most potent inhibitor against AChE (electrophorus electricus (eeAChE) half maximal inhibitory concentration (IC50) = 37.02 nM), it was also a strong inhibitor against BuChE (equine serum (eqBuChE) IC50 = 101.40 nM). Besides, it inhibited amyloid β-protein self-aggregation by 65.49% at 25 μM. In subsequent in vivo scopolamine-induced AD models, compound 10g obviously ameliorated the cognition impairment and showed preliminary safety in hepatotoxicity evaluation. These data suggest compound 10g as a promising multifunctional agent in the drug discovery process against AD.

Revisiting the Cholinergic Hypothesis in Alzheimer's Disease: Emerging Evidence from Translational and Clinical Research.

Scientific evidence collected over the past 4 decades suggests that a loss of cholinergic innervation in the cerebral cortex of patients with Alzheimer's disease is an early pathogenic event correlated with cognitive impairment. This evidence led to the formulation of the "Cholinergic Hypothesis of AD" and the development of cholinesterase inhibitor therapies. Although approved only as symptomatic therapies, recent studies suggest that long-term use of these drugs may also have disease-modifying benefits. A Cholinergic System Workgroup reassessed the role of the cholinergic system on AD pathogenesis in light of recent data, including neuroimaging data charting the progression of neurodegeneration in the cholinergic system and suggesting that cholinergic therapy may slow brain atrophy. Other pathways that contribute to cholinergic synaptic loss and their effect on cognitive impairment in AD were also reviewed. These studies indicate that the cholinergic system as one of several interacting systems failures that contribute to AD pathogenesis.

Scopolamine-induced passive avoidance memory retrieval deficit is accompanied with hippocampal MMP2, MMP-9 and MAPKs alteration

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive loss of memory and cognitive deficit. The observed amnesia in the early stages of AD is suggested to be a retrieval problem, rather than encoding and consolidation deficit. According to the cholinergic hypothesis of AD, scopolamine is used to induce an animal model of amnesia. Howbeit the effect of scopolamine on memory retrieval is contradictory. This study aimed to assess the effect of scopolamine on passive avoidance memory retrieval. Additionally according to the reported changes of MMP-2, MMP-9 and MAPKs (ERK, P38 and JNK) in AD pathology the hippocampal contents of these proteins were determined. Male NMRI mice weighing 20–25g were trained in passive avoidance apparatus. The drug or its vehicle was injected 24h after training (30min before retention test). The hippocampal tissue was isolated and western blot analysis was done for MMP-2, MMP-9 and MAPKs (ERK, P38 and JNK). The results indicated that scopolamine (1mg/kg) disrupts passive avoidance memory retrieval. This scopolamine treatment resulted in hippocampal MMP-2 and MMP-9 decline while increased MAPKs in the hippocampus. These results suggest that cholinergic system has an important role in learnt memory retrieval. It might also suggest the positive role of MMP-2 and MMP-9 in this phase of memory while propose that MAPKs affect negatively the reactivation of memory which is compatible with MAPKs activation in AD.

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USING CSF MARKERS TO VALIDATE METABOLIC AND SYNAPTIC DYSFUNCTION HYPOTHESES OF ALZHEIMER’S DISEASE (AD): META-ANALYSIS

Alzheimer's disease (AD) is currently incurable and a majority of investigational drugs have failed clinical trials. One explanation for this failure is the invalidity of some hypotheses explaining AD pathogenesis. Recently, hypotheses centered on synaptic and metabolic dysfunction are increasingly implicated in AD. Importantly, these hypotheses can readily be validated using neurotransmitter and metabolite biomarkers. Meta-analysis allows for statistical comparison of existing CSF biomarker data extracted from multiple publications, providing a unique opportunity to rapidly validate AD hypotheses in silico. Pubmed and Google Scholar were comprehensively searched for published English articles, without date restrictions, for the keywords “AD”, “CSF”, and “human” plus biomarkers selected for synaptic and metabolic pathways. Synaptic biomarkers were acetylcholine, GABA, glutamine, and glycine. Metabolic biomarkers were glutathione, glucose, lactate, pyruvate, and 8 other amino acids. Only studies that measured biomarkers in both AD and controls, provided means, standard errors/deviation, and subject numbers were included. Data were extracted by six authors and checked by two for accuracy. The data were transformed to log ratio of the means (AD/Control) and analyzed by the random effects model in the meta-analysis software (Cochrane Review Manager). Of 435 identified publications, after exclusion and removal of duplicates, 35 articles were included comprising a total of 605 AD patients and 585 controls. The following biomarkers for synaptic and metabolic pathways were significantly changed in AD/controls: acetylcholine (average ratio 0.36, 95% CI 0.24–0.53, p<0.00001), GABA (0.68, 0.54–0.85, p<0.0008), pyruvate (0.48, 0.24–0.94, p=0.03), glutathione (1.11, 1.01–1.21, p=0.03), alanine (1.10, 0.98–1.23, p=0.09), and lactate (1.17, 0.98–1.39, p=0.09). This study provides proof of concept for the use of meta-analysis validation of AD hypotheses, specifically via robust evidence for the cholinergic hypothesis of AD. Our data disagree with the other synaptic hypotheses of glutamate excitotoxicity (normal glutamate) and GABAergic resistance to neurodegeneration (decreased GABA levels). With regards to metabolic hypotheses, the data supported upregulation of anaerobic glycolysis, pentose phosphate pathway (glutathione), and TCA anaplerosis (several metabolites involved). Future applications of meta-analysis indicate the possibility of further in silico evaluation and generation of novel hypotheses in the AD field.

Exploration of the Acetylcholinesterase Inhibitory Activity of Some Alkaloids from Amaryllidaceae Family by Molecular Docking In Silico.

Alzheimer's disease (AD) is a progressive condition, where dementia symptoms gradually worsen. Biochemically the disease is characterized by the presence of neuritic plaques, neurofibrillary tangles, in addition to cholinergic dysfunction in the central nervous system. The role of the cholinergic neurotransmission in AD is the basis of the widely accepted cholinergic hypothesis. Some of the most relevant therapies for the treatment of the disease are based on the acetylcholinesterase (AChE) inhibitor activity; however, these therapies are not effective to stop the disease progression, but only can temporarily slow down the worsening of dementia symptoms, and improve quality of life of patients and their caregivers. In recent years, plant alkaloids extracted from Amaryllidaceae family have received great attention due to the well-known anti cholinergic activity. In this context, the purpose of this study was to apply the docking molecular in sílico analysis aiming to examine the recombinant human AChE enzyme (rhAChE) inhibitory activity displayed by different alkaloids from Amaryllidaceae family. Overall, the present results support the idea that alkaloids reported in this research are capable of interacting with rhAChE-binding sites.

Cardioprotective Action of Ginkgo biloba Extract against Sustained β-Adrenergic Stimulation Occurs via Activation of M2/NO Pathway.

Ginkgo biloba is the most popular phytotherapic agent used worldwide for treatment of several human disorders. However, the mechanisms involved in the protective actions of Ginkgo biloba on cardiovascular diseases remain poorly elucidated. Taking into account recent studies showing beneficial actions of cholinergic signaling in the heart and the cholinergic hypothesis of Ginkgo biloba-mediated neuroprotection, we aimed to investigate whether Ginkgo biloba extract (GBE) promotes cardioprotection via activation of cholinergic signaling in a model of isoproterenol-induced cardiac hypertrophy. Here, we show that GBE treatment (100 mg/kg/day for 8 days, v.o.) reestablished the autonomic imbalance and baroreflex dysfunction caused by chronic β-adrenergic receptor stimulation (β-AR, 4.5 mg/kg/day for 8 days, i.p.). Moreover, GBE prevented the upregulation of muscarinic receptors (M2) and downregulation of β1-AR in isoproterenol treated-hearts. Additionally, we demonstrated that GBE prevents the impaired endothelial nitric oxide synthase activity in the heart. GBE also prevented the pathological cardiac remodeling, electrocardiographic changes and impaired left ventricular contractility that are typical of cardiac hypertrophy. To further investigate the mechanisms involved in GBE cardioprotection in vivo, we performed in vitro studies. By using neonatal cardiomyocyte culture we demonstrated that the antihypertrophic action of GBE was fully abolished by muscarinic receptor antagonist or NOS inhibition. Altogether, our data support the notion that antihypertrophic effect of GBE occurs via activation of M2/NO pathway uncovering a new mechanism involved in the cardioprotective action of Ginkgo biloba.

Chalcone-based carbamates for Alzheimer's disease treatment.

Alzheimer's disease is a still untreatable multifaceted pathology, and drugs able to stop or reverse its progression are urgently needed. In this picture, the recent reformulation of the cholinergic hypothesis renewed the interest for acetylcholinesterase inhibitors. In this paper, a series of naturally inspired chalcone-based carbamates was designed to target cholinesterase enzymes and possibly generate fragments endowed with neuroprotective activity in situ. Results & methodology: All compounds presented in this study showed nanomolar potency for cholinesterase inhibition. Notably, fragment 11d also displayed an interesting neuroprotective profile. These new derivatives are able to simultaneously modulate different key targets involved in Alzheimer's disease, and could be regarded as promising starting points for the development of disease-modifying drug candidates. [Formula: see text].

A second wind for the cholinergic system in Alzheimer's therapy.

Notwithstanding tremendous research efforts, the cause of Alzheimer's disease (AD) remains elusive and there is no curative treatment. The cholinergic hypothesis presented 35 years ago was the first major evidence-based hypothesis on the etiology of AD. It proposed that the depletion of brain acetylcholine was a primary cause of cognitive decline in advanced age and AD. It relied on a series of observations obtained in aged animals, elderly, and AD patients that pointed to dysfunctions of cholinergic basal forebrain, similarities between cognitive impairments induced by anticholinergic drugs and those found in advanced age and AD, and beneficial effects of drugs stimulating cholinergic activity. This review revisits these major results to show how this hypothesis provided the drive for the development of anticholinesterase inhibitor-based therapies of AD, the almost exclusively approved treatment in use despite transient and modest efficacy. New ideas for improving cholinergic therapies are also compared and discussed in light of the current revival of the cholinergic hypothesis on the basis of two sets of evidence from new animal models and refined imagery techniques in humans. First, human and animal studies agree in detecting signs of cholinergic dysfunctions much earlier than initially believed. Second, alterations of the cholinergic system are deeply intertwined with its reactive responses, providing the brain with efficient compensatory mechanisms to delay the conversion into AD. Active research in this field should provide new insight into development of multitherapies incorporating cholinergic manipulation, as well as early biomarkers of AD enabling earlier diagnostics. This is of prime importance to counteract a disease that is now recognized to start early in adult life.

Potential acetylcholinesterase inhibitors: molecular docking, molecular dynamics, and in silico prediction.

This paper deals with molecular modeling of new therapeutic agents for treating the Alzheimer's disease. The therapeutic line adopted for this study is the cholinergic hypothesis. To modulate positively the cholinergic function through the inhibition of the acetylcholinesterase, a set of candidates was designed from a natural compound extracted from the cashew nutshell liquid, anacardic acid. In silico screening of this chemical library revealed a ligand that is more promising once it is correlated with an active drug through specific topological and electronic descriptors. The protein-ligand docking showed stable binding modes and the binding free energy computed for the active site of the receptor suggests that our ligand presents a potential biological response. Graphical Abstract Representation of the three dimensional structure of the AChE, showing the important binding sites of the Gorge and the conformation of the ligand.

Computational Screening and Exploration of Disease-Associated Genes in Alzheimer's Disease.

Alzheimer's is a neurodegenerative disease affecting large populations worldwide characterized mainly by progressive loss of memory along with various other symptoms. The foremost cause of the disease is still unclear, however various mechanisms have been proposed to cause the disease that include amyloid hypothesis, tau hypothesis, and cholinergic hypothesis in addition to genetic factors. Various genes have been known to be involved which are APOE, PSEN1, PSEN2, and APP among others. In the present study, we have used computational methods to examine the pathogenic effects of non-synonymous single nucleotide polymorphisms (SNPs) associated with ABCA7, CR1, MS4A6A, CD2AP, PSEN1, PSEN2, and APP genes. The SNPs were obtained from dbSNP database followed by identification of deleterious SNPs and prediction of their functional impact. Prediction of disease-associated mutations was performed and the impact of the mutations on the stability of the protein was carried out. To study the structural significance of the computationally prioritized mutations on the proteins, molecular dynamics simulation studies were carried out. On analysis, the SNPs with IDs rs76282929 ABCA7; CR1 rs55962594; MS4A6A rs601172; CD2AP rs61747098; PSEN1 rs63750231, rs63750265, rs63750526, rs63750577, rs63750687, rs63750815, rs63750900, rs63751037, rs63751163, rs63751399; PSEN2 rs63749851; and APP rs63749964, rs63750066, rs63750734, and rs63751039 were predicted to be deleterious and disease-associated having significant structural impact on the proteins. The current study proposes a precise computational methodology for the identification of disease-associated SNPs. J. Cell. Biochem. 118: 1471-1479, 2017. © 2016 Wiley Periodicals, Inc.

Molecular Anti-inflammatory Mechanisms of Retinoids and Carotenoids in Alzheimer's Disease: a Review of Current Evidence.

Alzheimer's disease (AD) is considered as one of the most prevalent neurodegenerative disorders characterized by progressive loss of mental function and ability to learn. AD is a multifactorial disorder. Various hypotheses are suggested for the pathophysiology of AD including "Aβ hypothesis," "tau hypothesis," and "cholinergic hypothesis." Recently, it has been demonstrated that neuroinflammation is involved in the pathogenesis of AD. Neuroinflammation causes synaptic dysfunction and neuronal death within the brain. Excessive production of pro-inflammatory mediators induces Aβ peptide production/accumulation and hyperphosphorylated tau generating inflammatory molecules and cytokines. These inflammatory molecules disrupt blood-brain barrier integrity and increase the production of Aβ42 oligomers. Retinoids and carotenoids are potent antioxidants and anti-inflammatory agents having neuroprotective properties. They are able to prevent disease progression through several mechanisms such as suppression of Aβ peptide production/accumulation, oxidative stress, and pro-inflammatory mediator's secretion as well as improvement of cognitive performance. These observations, therefore, confirm the neuroprotective role of retinoids and carotenoids through multiple pathways. Therefore, the administration of these nutrients is considered as a promising approach to the prevention and/or treatment of AD in the future. The aim of this review is to present existing evidences regarding the beneficial effects of retinoids and carotenoids on AD's risk and outcomes, seeking the mechanism of their action.