Formation Of Senile Plaques Research Articles

Molecular Mechanisms of ER Stress and UPR in the Pathogenesis of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease involving aggregation of misfolded proteins inside the neuron causing prolonged cellular stress. The neuropathological hallmarks of AD include the formation of senile plaques and neurofibrillary tangles in specific brain regions that lead to synaptic loss and neuronal death. The exact mechanism of neuron dysfunction in AD remains obscure. In recent years, endoplasmic reticulum (ER) dysfunction has been implicated in neuronal degeneration seen in AD. Apart from AD, many other diseases also involve misfolded proteins aggregations in the ER, a condition referred to as ER stress. The response of the cell to ER stress is to activate a group of signaling pathways called unfolded protein response (UPR) that stimulates a particular transcriptional program to restore ER function and ensure cell survival. ER stress also involves the generation of reactive oxygen species (ROS) that, together with mitochondrial ROS and decreased effectiveness of antioxidant mechanisms, producing a condition of chronic oxidative stress. The unfolded proteins may not always produce a response that leads to the restoration of cellular functions, but they may also lead to inflammation by a set of different pathways with deleterious consequences. In this review, we extensively discuss the role of ER stress and how to target it using different pharmacological approaches in AD development and onset.

Paper-Based Platform with an In Situ Molecularly Imprinted Polymer for β-Amyloid.

Alzheimer’s disease (AD) is one of the most common forms of dementia affecting millions of people worldwide. Currently, an easy and effective form of diagnosis is missing, which significantly hinders a possible improvement of the patient’s quality of life. In this context, biosensors emerge as a future solution, opening the doors for preventive medicine and allowing the premature diagnosis of numerous pathologies. This work presents a pioneering biosensor that combines a bottom-up design approach using paper as a platform for the electrochemical recognition of peptide amyloid β-42 (Aβ-42), a biomarker for AD present in blood, associated with visible differences in the brain tissue and responsible for the formation of senile plaques. The sensor layer relies on a molecularly imprinted polymer as a biorecognition element, created on the carbon ink electrode’s surface by electropolymerizing a mixture of the target analyte (Aβ-42) and a monomer (O-phenylenediamine) at neutral pH 7.2. Next, the template molecule was removed from the polymeric network by enzymatic and acidic treatments. The vacant sites so obtained preserved the shape of the imprinted protein and were able to rebind the target analyte. Morphological and chemical analyses were performed in order to control the surface modification of the materials. The analytical performance of the biosensor was evaluated by an electroanalytical technique, namely, square wave voltammetry. For this purpose, the analytical response of the biosensor was tested with standard solutions ranging from 0.1 ng/mL to 1 μg/mL of Aβ-42. The linear response of the biosensor went down to 0.1 ng/mL. Overall, the developed biosensor offered numerous benefits, such as simplicity, low cost, reproducibility, fast response, and repeatability less than 10%. All together, these features may have a strong impact in the early detection of AD.

Effect of electroacupuncture on the expression of insulin signal pathway related proteins in hippocampus in mice with Alzheimer's disease

To observe the effect of electroacupuncture (EA) on the expression of insulin phosphatidylinositol-3 kinase/glycogen synthetase kinase-3α (PI3K/GSK3α) signal pathway related proteins in the hippocampus in mice with Alzheimer's disease (AD), and to explore the regulatory mechanism of EA on improving the pathological characteristics of AD. Twelve male APP/PS1 double transgenic mice were randomly divided a model group and a treatment group, 6 mice in each group; another 6 wild-type male mice were taken as the control group. The mice in the treatment group were treated with EA (continuous wave, 2 Hz of frequency) at "Baihui" (GV 20) and bilateral "Shenshu" (BL 23), once a day; 7-day treatment was taken as a course of treatment, and 2 courses of treatment were given. The immunohistochemistry method and Western blot method were used to detect the distribution and expression level of hippocampal PI3K/GSK3α signal pathway related proteins P85α, P110α, GSK3α and pS21GSK3α, and the number of hippocampal senile plaques (SP) was observed. The proteins of P85α, P110α, GSK3α and pS21GSK3α were mainly distributed in the cytoplasm of hippocampal neurons, and the GSK3α was also distributed in the axons of neurons in the model group and the treatment group. The immunohistochemistry results showed that the distribution level of GSK3α in the hippocampus in the model group was significantly higher than that in the control group (P<0.001), and the distribution level of pS21GSK3α, P85α and P110α was significantly decreased (P<0.01, P<0.001); compared with the model group, the distribution level of GSK3α in the hippocampus in the treatment group was significantly decreased (P<0.001), and the distribution level of pS21GSK3α, P85α and P110α in hippocampus was significantly increased (P<0.05, P<0.001). The Western blot results showed compared with the control group, the expression of pS21GSK3α, P85α and P110α as well as the ratio of pS21GSK3α/GSK3α in the hippocampus in the model group were significantly decreased (P<0.001), and the expression of GSK3α was increased (P<0.05); compared with the model group, the expression of pS21GSK3α, P85α, P110α and the ratio of pS21GSK3α/GSK3α in the hippocampus in the treatment group were significantly increased (P<0.01, P<0.001), and the expression of GSK3α was decreased (P<0.05). Compared with the control group, the number of hippocampal SP in the model group was significantly increased (P<0.001); compared with the model group, the number of hippocampal SP in the treatment group was significantly decreased (P<0.01). EA could effectively regulate the expression of PI3K/GSK3α signal pathway related proteins in the hippocampus in mice with AD, so as to reduce the formation and deposition of SP.

Bioinformatics Review of the Role of HSV-1 in Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the progressive loss of cognitive functions in affected individuals. Brain tissue pathology is associated with the formation of senile plaques which result from the over-production of amyloid β (Aβ), due to the cleavage of a membrane bound glycoprotein. It is unclear what causes AD and its associated pathologies, but age and genetic predisposition play an import role in the likelihood of disease development. Studies have shown that the reactivation of latent herpes simplex virus 1 (HSV-1) infection can lead to the neuropathy of acute herpes simplex encephalitis (HSE), which causes similar symptoms to AD. HSV-1 infection is a known risk factor for the development of AD, but no study has determined a definitive causal relationship. Using the Qiagen Ingenuity Pathway Analysis (IPA) tool, the inhibitory relationship between therapeutics for AD and HSV-1 were explored. Thirteen drugs developed to decrease Aβ buildup in AD and 32 drugs that act as HSV antivirals were retrieved from the data in the Qiagen Knowledge Base. These drugs were analyzed displayed as two separate networks. While many promising Aβ aggregation-targeting drugs have been discontinued due to lack of efficacy, HSV drugs could serve as potential therapeutics for those with AD. This review aims to describe new insights on how HSV-1 relates to the development of AD and highlight the mechanism of action of Aβ-related drugs and HSV drugs in the context of AD. With HSV-1 being a likely candidate for the causation of AD, there is a need to study the effects of HSV antiviral drugs on those who have AD.

Ovarian Hormone-Dependent Effects of Dietary Lipids on APP/PS1 Mouse Brain.

The formation of senile plaques through amyloid-β peptide (Aβ) aggregation is a hallmark of Alzheimer’s disease (AD). Irrespective of its actual role in the synaptic alterations and cognitive impairment associated with AD, different therapeutic approaches have been proposed to reduce plaque formation. In rodents, daily intake of omega-3 (n-3) long-chain polyunsaturated fatty acids (LC-PUFAs) is required for neural development, and there is experimental and epidemiological evidence that their inclusion in the diet has positive effects on several neurodegenerative diseases. Similarly, estradiol appears to reduce senile plaque formation in primary mouse cell cultures, human cortical neurons and mouse AD models, and it prevents Aβ toxicity in neural cell lines. We previously showed that differences in dietary n-6/n-3 LC-PUFAs ratios modify the lipid composition in the cerebral cortex of female mice and the levels of amyloid precursor protein (APP) in the brain. These effects depended in part on the presence of circulating estradiol. Here we explored whether this potentially synergistic action between diet and ovarian hormones may influence the progression of amyloidosis in an AD mouse model. Our results show that a diet with high n-3 LC-PUFA content, especially DHA (22:6n-3), reduces the hippocampal accumulation of Aβ1–40, but not amyloid Aβ1–42 in female APPswe/PS1 E9A mice, an effect that was counteracted by the loss of the ovaries and that depended on circulating estradiol. In addition, this interaction between dietary lipids and ovarian function also affects the composition of the brain lipidome as well as the expression of certain neuronal signaling and synaptic proteins. These findings provide new insights into how ovarian hormones and dietary composition affect the brain lipidome and amyloid burden. Furthermore, they strongly suggest that when designing dietary or pharmacological strategies to combat human neurodegenerative diseases, hormonal and metabolic status should be specifically taken into consideration as it may affect the therapeutic response.

Acetylation of Aβ40 Alters Aggregation in the Presence and Absence of Lipid Membranes.

A hallmark of Alzheimer's disease (AD) is the formation of senile plaques comprised of the β-amyloid (Aβ) peptide. Aβ fibrillization is a complex nucleation-dependent process involving a variety of metastable intermediate aggregates and features the formation of inter- and intramolecular salt bridges involving lysine residues, K16 and K28. Cationic lysine residues also mediate protein-lipid interactions via association with anionic lipid headgroups. As several toxic mechanisms attributed to Aβ involve membrane interactions, the impact of acetylation on Aβ40 aggregation in the presence and absence of membranes was determined. Using chemical acetylation, varying mixtures of acetylated and nonacetylated Aβ40 were produced. With increasing acetylation, fibril and oligomer formation decreased, eventually completely arresting fibrillization. In the presence of total brain lipid extract (TBLE) vesicles, acetylation reduced the interaction of Aβ40 with membranes; however, fibrils still formed at near complete levels of acetylation. Additionally, the combination of TBLE and acetylated Aβ promoted annular aggregates. Finally, toxicity associated with Aβ40 was reduced with increasing acetylation in a cell culture assay. These results suggest that in the absence of membranes that the cationic character of lysine plays a major role in fibril formation. However, acetylation promotes unique aggregation pathways in the presence of lipid membranes.

PYRAZOLINE CONTAINING MOLECULES AS MULTIFUNCTIONAL AGENTS IN ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is a progressive, neurodegenerative disease which is caused mainly due to accumulation of an aberrant protein known as β-amyloid in the form of senile plaques. However, over the past few years, network biology studies have indicated that classical “one drug-one target” hypothesis may not work in diseases such as AD where the biochemical disease mechanisms are intricately interconnected. therefore, multifunctional molecules which can modulate several targets could be the key towards finding the therapeutics for this debilitating disorder. Keeping this in mind, several pyrazoline containing molecules with promising Aβ aggregation inhibition potential were explored further against key targets involved in AD, such as cholinesterases, oxidative stress and advanced glycation end products (AGe). Some potential multifunctional molecules were identified as a result of this work.

A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of Teprenone in Patients with Alzheimer's Disease.

Teprenone (geranylgeranylacetone), an anti-ulcer agent, has been reported to inhibit amyloid-β increase, senile plaque formation, and neuronal degeneration, and improve memory in mouse models of Alzheimer's disease (AD). We conducted a randomized, double-blind, placebo-controlled study to ascertain teprenone's therapeutic ability for AD. Patients with mild to moderate AD, with a Mini-Mental State Examination (MMSE) score of 13 to 26, were randomly allocated into two groups depending on the administered drug: donepezil + placebo (placebo group) and donepezil + teprenone (teprenone group). The primary and secondary endpoints included changes in scores of the Japanese version of the AD Assessment Scale-cognitive subscale (ADAS-J cog) and other evaluations, respectively, including MMSE scores, during a 12-month period after the first administration. Forty-two and thirty-seven patients were allocated to the teprenone and placebo groups, respectively. ADAS-J cog score changes were not different between groups (placebo, 0.6±0.8; teprenone, 0.4±0.8; p = 0.861). However, MMSE scores significantly improved in the teprenone group (placebo, - 1.2±0.5; teprenone, 0.2±0.5; p = 0.044). Subgroup analysis considering the severity of medial temporal area atrophy revealed that this improvement by teprenone was significant in patients with mild (p = 0.013) but not with severe atrophy (p = 0.611). Adverse events were observed in 17.8 and 10.4% of patients in the placebo and teprenone group, respectively. Teprenone may be effective for AD when administered before atrophy progression in the medial temporal areas. UMIN ID: UMIN000016843.

Ginsenoside Re Inhibits ROS/ASK-1 Dependent Mitochondrial Apoptosis Pathway and Activation of Nrf2-Antioxidant Response in Beta-Amyloid-Challenged SH-SY5Y Cells.

Accumulation of amyloid-β (Aβ), which results in the formation of senile plaques that cause oxidative damage and neuronal cell death, has been accepted as the major pathological mechanism of Alzheimer’s disease (AD). Hence, inhibition of Aβ-induced oxidative damage and neuronal cell apoptosis represents the effective strategies in combating AD. Ginsenoside Re (Re) has pharmacological effects against Aβ-induced neurotoxicity. However, its molecular mechanism remains elusive. The present study evaluated the effect of Re against Aβ-induced cytotoxicity and apoptosis in SH-SY5Y cells, and investigated the underlying mechanism. We demonstrate that Re inhibits the Aβ-triggered mitochondrial apoptotic pathway, as indicated by maintenance of mitochondrial functional, elevated Bcl-2/Bax ratio, reduced cytochrome c release, and inactivation of caspase-3/9. Re attenuated Aβ-evoked reactive oxygen species (ROS) production, apoptosis signal-regulating kinase 1 (ASK1) phosphorylation, and JNK activation. ROS-scavenging abrogated the ability of Re to alter ASK-1 activation. Simultaneously, inhibition of JNK abolished Re-induced Bax downregulation in Aβ-challenged SH-SY5Y cells. In addition, Re enhanced activation of the nuclear factor-E2-related factor 2 (Nrf2) in Aβ-induced SH-SY5Y cells. Knockdown of Nrf2 by small interfering RNA targeting Nrf2 abolished the protective effect of Re. Our findings indicate that Re could be a potential therapeutic approach for the treatment of AD.

Hydrogen Peroxide Modifies Aβ-Membrane Interactions with Implications for Aβ40 Aggregation.

Alzheimer's disease (AD) is pathologically characterized by the formation of extracellular senile plaques, predominately comprised of aggregated β-amyloid (Aβ), deposited in the brain. Aβ aggregation can result in a myriad of distinct aggregate species, from soluble oligomers to insoluble fibrils. Aβ strongly interacts with membranes, which can be linked to a variety of potential toxic mechanisms associated with AD. Oxidative damage accompanies the formation of Aβ aggregates, with a 10-50% proportion of Aβ aggregates being oxidized in vivo. Hydrogen peroxide (H2O2) is a reactive oxygen species implicated in a number of neurodegenerative diseases. Recent evidence has demonstrated that the H2O2 concentration fluctuates rapidly in the brain, resulting in large concentration spikes, especially in the synaptic cleft. Here, the impact of environmental H2O2 on Aβ aggregation in the presence and absence of lipid membranes is investigated. Aβ40 was exposed to H2O2, resulting in the selective oxidation of methionine 35 (Met35) to produce Aβ40Met35[O]. While oxidation mildly reduced the rate of Aβ aggregation and produced a distinct fibril morphology at high H2O2 concentrations, H2O2 had a much more pronounced impact on Aβ aggregation in the presence of total brain lipid extract vesicles. The impact of H2O2 on Aβ aggregation in the presence of lipids was associated with a reduced affinity of Aβ for the vesicle surface. However, this reduced vesicle affinity was predominately associated with lipid peroxidation rather than Aβ oxidation.

Flavanone glycosides inhibit β-site amyloid precursor protein cleaving enzyme 1 and cholinesterase and reduce Aβ aggregation in the amyloidogenic pathway

Alzheimer's disease (AD) is a slow but progressive neurodegenerative disease. One of the pathological hallmarks of AD is the progressive accumulation of β-amyloid (Aβ) in the form of senile plaques, and Aβ insult to neuronal cells has been identified as one of the major causes of AD onset. In the present study, we investigated the anti-AD potential of four flavonoids, naringenin, didymin, prunin, and poncirin, by evaluating their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein cleaving enzyme 1 (BACE1). All four flavonoids displayed promising inhibitory activity against AChE, BChE, and BACE1. Structure–activity relationships suggested that glycosylation of naringenin at sugar moieties, and at different positions of the glycosidic linkage, might be closely associated with anti-AD potential. Kinetic and docking studies showed the lowest binding energy and highest affinity for the mixed, competitive, and non-competitive type inhibitors didymin, prunin, and poncirin. Hydrophobic interactions and the number of hydrogen bonds determined the strength of the protein–inhibitor interaction. We also examined the neuroprotective mechanisms by which flavonoids act against Aβ25–35-induced toxicity in PC12 cells. Exposure of PC12 cells to 10 μM Aβ25–35 for 24 h resulted in a significant decrease in cell viability. In addition, pretreatment of PC12 cells with different concentrations of flavonoids for 1 h significantly reversed the effects of Aβ. Furthermore, treatment with the most active flavonoid, didymin, significantly reduced BACE1, APPsβ, and C99 expression levels in a dose-dependent manner, without affecting amyloid precursor protein (APP) levels in the amyloidogenic pathway. Together, our results indicate that flavonoids, and in particular didymin, exhibit inhibitory activity in vitro, and may be useful in the development of therapeutic modalities for the treatment of AD.

Axonopathy Likely Initiates Neuropathological Processes Via a Mechanism of Axonal Leakage in Alzheimer's Mouse Models.

The formation of hyperphosphorylated tau and the production of β-amyloid are thought to be critical steps contributing to the pathological mechanisms in Alzheimer's disease (AD). However, there has been a long-lasting debate over their importance in the onset of AD. Recent studies have demonstrated that axonopathy is considered as an early neuropathological change of AD. However, the exact relationship between the development of axonopathy and the classic neuropathological changes such as senile plaques (SPs) and neurofibrillary tangles (NFTs) is unclear. The aim of this study was to investigate whether the formation of SPs and NFTs is associated with the development of axonal leakage. Here we show that the formation and development of axonal leakage - a novel axonopathy is an age-dependent process, accompanied by swellings of axons and varicosities and associated with chronic oxidative stress induced by thiamine deficient (TD) diet in Kunming mice. In an APP/PS1 transgenic mouse model of AD, axonal leakage appears at 3 months, becomes more obvious at 6 months and severe, beyond 1 year. We also show that slight axonal leakage is related to the formation of hyperphosphorylated tau, but not plaques, and that only severe axonal leakage accompanied by the extensive swollen axons and varicosities, and overproduction of β-amyloid leads to the formation of SPs and hyperphosphorylated tau. These data provide an explanation of the common origin and development of SPs and NFTs, and suggest that axonal leakage might be a key event in the development of the neuropathological processes in AD.

Nitazoxanide, an anti-parasitic drug, efficiently ameliorates learning and memory impairments in AD model mice.

The pathogenesis of Alzheimer's disease (AD) is characterized by both accumulation of β-amyloid (Aβ) plaque and formation of neurofibrillary tangles in the brain. Recent evidence shows that autophagy activation may potently promote intracellular Aβ clearance. Thus targeting autophagy becomes a promising strategy for discovery of drug leads against AD. In the present study, we established a platform to discover autophagy stimulator and screened the lab in-house FDA-approved drug library. We found that anti-parasitic drug nitazoxanide (NTZ) was an autophagy activator and could efficiently improve learning and memory impairments in APP/PS1 transgenic mice. In BV2 cells and primary cortical astrocytes, NTZ stimulated autophagy and promoted Aβ clearance by inhibiting both PI3K/AKT/mTOR/ULK1 and NQO1/mTOR/ULK1 signaling pathways; NTZ treatment attenuated LPS-induced inflammation by inhibiting PI3K/AKT/IκB/NFκB signaling. In SH-SY5Y cells and primary cortical neurons, NTZ treatment restrained tau hyperphosphorylation through inhibition of PI3K/AKT/GSK3β pathway. The beneficial effects and related signaling mechanisms from the in vitro studies were also observed in APP/PS1 transgenic mice following administration of NTZ (90 mg·kg-1·d-1, ig) for 100 days. Furthermore, NTZ administration decreased Aβ level and senile plaque formation in the hippocampus and cerebral cortex of APP/PS1 transgenic mice, and improved learning and memory impairments in Morris water maze assay. In conclusion, our results highlight the potential of NTZ in the treatment of AD.

Supplementation with Curcuma longa Reverses Neurotoxic and Behavioral Damage in Models of Alzheimer's Disease: A Systematic Review.

Background: The formation of senile plaques and neurofibrillary tangles of the tau protein are the main pathological mechanism of Alzheimer’s disease (AD). Current therapies for AD offer discrete benefits to the clinical symptoms and do not prevent the continuing degeneration of neuronal cells. Therefore, novel therapeutic strategies have long been investigated, where curcumin (Curcuma longa) has shown some properties that can prevent the deleterious processes involved in neurodegenerative diseases.Objective: The aim of the present work is to review studies that addressed the effects of curcumin in experimental models (in vivo and in vitro) for AD.Method: This study is a systematic review conducted between January and June 2017, in which a consultation of scientific articles from indexed periodicals was carried out in Science Direct, United States National Library of Medicine (PubMed), Cochrane Library and Scielo databases, using the following descriptors: “Curcuma longa”, “Curcumin” and “Alzheimer’s disease”.Results: A total of 32 studies were analyzed, which indicated that curcumin supplementation reverses neurotoxic and behavioral damages in both in vivo and in vitro models of AD.Conclusion: The administration of curcumin in experimental models seems to be a promising approach in AD, even though it is suggested that additional studies must be conducted using distinct doses and through other routes of administration.

Vildagliptine protects SH-SY5Y human neuron-like cells from Aβ 1-42 induced toxicity, in vitro.

The amyloid β (Aβ) toxic fibrils is thought to play a central role in the onset and progression of Alzheimer's disease (AD) because of it is a main formation of senile plaques. Diabetic patients are more vulnerable to caught Alzheimer's disease. Vildagliptine, a novel anti diabetic agent, has been reported to exert protective effects on AD rat models in restricted study. We aimed to investigate any protective effects of vildagliptine against Aβ fibrils on SH-SY5Y cell line. Vildagliptine decreased PSEN1 and PSEN2 mRNA levels which enroll Aβ production. In addition, vildagliptin was downregulated caspase-3 and caspase-9 expression levels which were evoked by Aβ. Also we confirmed cellular viability with real time cell analyzer and MTT assay. Our data exposed that vildagliptine has lowering effect on GSK3β and Tau phosphorylation. However we did not get protective effect of vildagliptine against Aβ toxicity on mitochondrial membrane potential. These results indicate that vildagliptine exerts a protective effect against Aβ by decreasing apoptosis related proteins, lowering GSK3β and Tau phosphorylation levels in addition to expression of PSEN1 and PSEN2 mRNA downregulation effect.

Protection against Neurodegeneration in the Hippocampus Using Sialic Acid- and 5-HT-Moduline-Conjugated Lipopolymer Nanoparticles.

Significant involvement of oxidative stress in the brain can develop Alzheimer's disease (AD); however, a great number of clinical trials explains the limited success of antioxidant therapy in dealing with this neurodegenerative disease. Here, we established a lipopolymer system of poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) incorporated with phosphatidic acid (PA) and modified with sialic acid (SA) and 5-hydroxytryptamine-moduline (5HTM) to improve quercetin (QU) activity against oxidative stress induced by amyloid-β (Aβ) deposits. Morphological studies revealed a uniform exterior of QU-SA-5HTM-PA-PLGA NPs with a spherical structure and enhanced aggregation with inclusion of PA in the formulation. A better brain-targeted delivery of the lipopolymeric NPs was verified from the high blood-brain barrier (BBB) permeability of QU through strong interactions of surface SA and 5HTM with O-linked N-acetylglucosamine and 5-HT1B receptors, respectively. Immunofluorescence staining images also supported QU-SA-5HTM-PA-PLGA NPs to traverse the microvessels of AD rat brain. Western blot analysis showed that QU-loaded PA-PLGA NPs suppressed caspase-3 expression. The ability of the nanocarriers to recognize Aβ fibrils was demonstrated from the reduced senile plaque formation and the attenuated acetylcholinesterase and malondialdehyde activity in the hippocampus. Hence, the medication of QU-SA-5HTM-PA-PLGA NPs can facilitate the BBB penetration and prevent Aβ accumulation, lipid peroxidation, and neuronal apoptosis for the AD management.

Glial S100A6 Degrades β-amyloid Aggregation through Targeting Competition with Zinc Ions

Evidence has been accumulating that zinc ions can trigger β-amyloid (Aβ) deposition and senile plaque formation in the brain, a pathological hallmark of Alzheimer’s disease (AD). Chelating zinc inhibits Aβ aggregation and may hold promise as a therapeutic strategy for AD. S100A6 is an acidic Ca2+/Zn2+-binding protein found only in a small number of astrocytes in the normal brain. However, in the AD brain, S100A6 is highly expressed in astrocytes around Aβ plaques. The role of the astrocytic S100A6 upregulation in AD is unknown. In the present study, we examined the effects of S100A6 on Aβ plaques and intracellular zinc levels in a mouse model of AD. Chronic exposure to zinc increased Aβ deposition and S100A6 expression, both reversible by the zinc chelator clioquinol, in the brains of amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice. To examine whether exogenous S100A6 could induce Aβ plaque disaggregation through competition for zinc in vitro, we incubated APP/PS1 mouse brain sections with recombinant human S100A6 protein or co-incubated them with human S100A6-expressing cells. Both treatments efficiently reduced the Aβ plaque burden in situ. In addition, treatment with exogenous S100A6 protected cultured COS-7 cells against zinc toxicity. Our results show for the first time that increased S100A6 levels correlate with both Aβ disaggregation and decrease of Aβ plaque-associated zinc contents in brain sections with AD-like pathology. Astrocytic S100A6 in AD may protect from Aβ deposition through zinc sequestration.

Computational and experimental studies on the interaction between butyrylcholinesterase and fluoxetine: implications in health and disease

Butyrylcholinesterase (BChE) is a serine esterase that plays a role in the detoxification of natural as well as synthetic ester-bond-containing compounds. Alterations in BChE activity are associated with a number of diseases. Cholinergic system abnormalities in particular are correlated with the formation of senile plaques in Alzheimer’s disease (AD), and administration of cholinesterase inhibitors is a common therapeutic approach used to treat AD.Here, our aim was to study the interaction between BChE and fluoxetine.Molecular docking simulations revealed that fluoxetine penetrated deep into the active-site gorge of BChE and that it was engaged in stabilizing noncovalent interactions with multiple subsites. In substrate kinetic studies, the Vm, Km, kcat and kcat/Km values were found to be 20.59 ± 0.36 U mg−1 protein, 194 ± 14 µM, 1.3 × 108 s−1 and 6.7 × 105 µM−1s−1, respectively. Based on inhibitory studies, fluoxetine appeared to inhibit BChE competitively, with an IC50 value of 104 µM and a Ki value of 36.3 ± 4.7 µM.Overall, both the low Ki value and the high number of BChE–fluoxetine interactions suggest that fluoxetine is a potent inhibitor of BChE, although in vivo mechanisms for the direct effects of BChE inhibition on various pathologies remain to be further investigated.

An updated review on Anti-Alzheimer’s herbal drugs

Alzheimer’s disease (AD) is related to cognitive impairment, dementia observed generally in aged population due to neurodegeneration in an ongoing manner. It gradually worsens memory power of the patient. The hallmark diagnosis features includes formation of senile plaques and Neurofibrillary tangles (NFT’S) [1, 2]. Too little availability of Acetyl choline (ACh) a neurotransmitter in the cerebral region due to metabolism by an enzyme Acetyl choline esterase before showing its action and neural death are the primary reasons for AD. There are many categories of Anti-Alzheimer’s drugs available for management of AD in the market but due to lack of patient compliance successful outcomes were not observed [3]. Apart from this including Nutraceuticals in diet daily routine, Aromatherapy, modifications in the regular schedule, practicing yoga regularly relaxes mind and body from tensions, insomnia, blood circulation, detoxification of organs due to rhythmic breathings and reduce frequency of incidence of headache are proven to show best results by relieving stress according to survey[4-9]. At present herbal medicine has turn out to be best choice for the management of AD because of its availability, very economic, good patient compliance, ease of formulation and lower deleterious side effects [10, 11]. Novel techniques can be used for the development of herbal medicine. This review totally discuses about the occurrence of AD, its Pathophysiology, different stages in the disorder, various selective therapeutic targets for AD, available Anti-AD herbal drugs such as Curcumin, Withania somnifera, Bhrami, Ginkgo biloba, guggul, ginseng, herbs with essential oils, volatile oils, source and cultivation of the herbs, mechanism of action of the Phytochemicals in the herb responsible for treating AD.&#x0D; Keywords: Alzheimer’s disease (AD), cognitive impairment, Dementia, Senile plaques, Nutraceuticals, Herbal medicine, Phytoconstituents.

Autophagic dysfunction in Alzheimer's disease: Cellular and molecular mechanistic approaches to halt Alzheimer's pathogenesis.

Autophagy is a preserved cytoplasmic self-degradation process and endorses recycling of intracellular constituents into bioenergetics for the controlling of cellular homeostasis. Functional autophagy process is essential in eliminating cytoplasmic waste components and helps in the recycling of some of its constituents. Studies have revealed that neurodegenerative disorders may be caused by mutations in autophagy-related genes and alterations of autophagic flux. Alzheimer's disease (AD) is an irrevocable deleterious neurodegenerative disorder characterized by the formation of senile plaques and neurofibrillary tangles (NFTs) in the hippocampus and cortex. In the central nervous system of healthy people, there is no accretion of amyloid β (Aβ) peptides due to the balance between generation and degradation of Aβ. However, for AD patients, the generation of Aβ peptides is higher than lysis that causes accretion of Aβ. Likewise, the maturation of autophagolysosomes and inhibition of their retrograde transport creates favorable conditions for Aβ accumulation. Furthermore, increasing mammalian target of rapamycin (mTOR) signaling raises tau levels as well as phosphorylation. Alteration of mTOR activity occurs in the early stage of AD. In addition, copious evidence links autophagic/lysosomal dysfunction in AD. Compromised mitophagy is also accountable for dysfunctional mitochondria that raises Alzheimer's pathology. Therefore, autophagic dysfunction might lead to the deposit of atypical proteins in the AD brain and manipulation of autophagy could be considered as an emerging therapeutic target. This review highlights the critical linkage of autophagy in the pathogenesis of AD, and avows a new insight to search for therapeutic target for blocking Alzheimer's pathogenesis.