Deposition Of Senile Plaques Research Articles

Immune modulations and immunotherapies for Alzheimer’s disease: a comprehensive review

Alzheimer's disease (AD), the most common cause of dementia, is characterized by progressive cognitive and memory impairment ensued from neuronal dysfunction and eventual death. Intraneuronal deposition of tau proteins and extracellular senile amyloid-β plaques have ruled as the supreme postulations of AD for a relatively long time, and accordingly, a wide range of therapeutics, especially immunotherapies have been implemented. However, none of them resulted in significant positive cognitive outcomes. Especially, the repetitive failure of anti-amyloid therapies proves the inefficiency of the amyloid cascade hypothesis, suggesting that it is time to reconsider this hypothesis. Thus, for the time being, the focus is being shifted to neuroinflammation as a third core pathology in AD. Neuroinflammation was previously considered a result of the two aforementioned phenomena, but new studies suggest that it might play a causal role in the pathogenesis of AD. Neuroinflammation can act as a double-edged sword in the pathogenesis of AD, and the activation of glial cells is indispensable for mediating such attenuating or detrimental effects. The association of immune-related genes polymorphisms with the clinical phenotype of AD as well as the protective effect of anti-inflammatory drugs like nonsteroidal anti-inflammatory drugs supports the possible causal role of neuroinflammation in AD. Here, we comprehensively review immune-based therapeutic approaches toward AD, including monoclonal antibodies and vaccines. We also discuss their efficacy and underlying reasons for shortcomings. Lastly, we highlight the capacity of modulating the neuroimmune interactions and targeting neuroinflammation as a promising opportunity for finding optimal treatments for AD.

Sequential conformational changes in transmembrane domains of presenilin 1 in Aβ42 downregulation.

Alzheimer disease (AD) is the most common neurodegenerative disease worldwide. AD is pathologically characterized by the deposition of senile plaques in the brain, which are composed of an amyloid-β peptide (Aβ) that is produced through the multistep cleavage of amyloid precursor protein (APP) by γ-secretase. γ-Secretase is a membrane protein complex, which includes its catalytic subunit presenilin 1 (PS1). However, much about the structural dynamics of this enzyme remain unclear. We have previously demonstrated that movements of the transmembrane domain (TMD) 1 and TMD3 of PS1 are strongly associated with decreased production of the Aβ peptide ending at the 42nd residue (i.e. Aβ42), which is the aggregation-prone, toxic species. However, the association between these movements as well as the sequence of these TMDs remains unclear. In this study, we raised the possibility that the vertical movement of TMD1 is a prerequisite for expansion of the catalytic cavity around TMD3 of PS1, resulting in reduced Aβ42 production. Our results shed light on the association between the conformational changes of TMDs and the regulation of γ-secretase activity.

Caspase-1/IL-1\u03b2 represses membrane transport of GluA1 by inhibiting the interaction between Stargazin and GluA1 in Alzheimer\u2019s disease

BackgroundAlzheimer's disease is a neurodegenerative disease. Previous study has reported that caspase-1/IL-1β is closely associated with Alzheimer's disease. However, the biological role of caspase-1/IL-1β in Alzheimer's disease has not been fully elucidated. This study aimed to explore the mechanism of action of caspase-1/IL-1β in Alzheimer's disease.MethodsMouse hippocampal neurones were treated with Aβ1-42 to induce Alzheimer's disease cell model. APP/PS1 mice and Aβ1-42-induced hippocampal neurones were treated with AC-YVAD-CMK (caspase-1 inhibitor). Spatial learning and memory ability of mice were detected by morris water maze. Flow cytometry, TUNEL staining, Thioflavin S staining and immunohistochemistry were performed to examine apoptosis and senile plaque deposition. Enzyme linked immunosorbent assay and western blot were performed to assess the levels of protein or cytokines. Co-Immunoprecipitation was performed to verify the interaction between Stargazin and GluA1.ResultsAC-YVAD-CMK treatment improved spatial learning and memory ability and reduced senile plaque deposition of APP/PS1 mice. Moreover, AC-YVAD-CMK promoted membrane transport of GluA1 in APP/PS1 mice. In vitro, Aβ1-42-induced hippocampal neurones exhibited an increase in apoptosis and a decrease in the membrane transport of GluA1, which was abolished by AC-YVAD-CMK treatment. In addition, Stargazin interacted with GluA1, which was repressed by caspase-1. Caspase-1/IL-1β inhibited membrane transport of GluA1 by inhibiting the interaction between Stargazin and GluA1.ConclusionsOur data demonstrate that caspase-1/IL-1β represses membrane transport of GluA1 by inhibiting the interaction between Stargazin in Alzheimer's disease. Thus, caspase-1/IL-1β may be a target for Alzheimer's disease treatment.

Anti-Aβ Antibody Aducanumab Regulates the Proteome of Senile Plaques and Closely Surrounding Tissue in a Transgenic Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by accumulation of amyloid-β (Aβ) species and deposition of senile plaques (SPs). Clinical trials with the anti-Aβ antibody aducanumab have been completed recently. To characterize the proteomic profile of SPs and surrounding tissue in a mouse model of AD in 10-month-old tgAPPPS1-21 mice after chronic treatment with aducanumab for four months with weekly dosing (10 mg/kg). After observing significant reduction of SP numbers in hippocampi of aducanumab-treated mice, we applied a localized proteomic analysis by combining laser microdissection and liquid chromatography-tandem mass spectrometry (LC-MS/MS) of the remaining SPs in hippocampi. We microdissected three subregions, containing SPs, SP penumbra level 1, and an additional penumbra level 2 to follow the proteomic profile as gradient. In the aducanumab-treated mice, we identified 17 significantly regulated proteins that were associated with 1) mitochondria and metabolism (ACAT2, ATP5J, ETFA, EXOG, HK1, NDUFA4, NDUFS7, PLCB1, PPP2R4), 2) cytoskeleton and axons (ADD1, CAPZB, DPYSL3, MAG), 3) stress response (HIST1H1C/HIST1H1D, HSPA12A), and 4) AβPP trafficking/processing (CD81, GDI2). These pathways and some of the identified proteins are implicated in AD pathogenesis. Proteins associated with mitochondria and metabolism were mainly upregulated while proteins associated with AβPP trafficking/processing and stress response pathways were mainly downregulated, suggesting that aducanumab could lead to a beneficial proteomic profile around SPs in tgAPPPS1-21 mice. We identified novel proteomic patterns of SPs and surrounding tissue indicating that chronic treatment with aducanumab could inhibit Aβ toxicity and increase phagocytosis and cell viability.

Recent Trends in the Management of Alzheimer's Disease: Current Therapeutic Options and Drug Repurposing Approaches.

Alzheimer’s disease is one of the most progressive forms of dementia, ultimately leading to death in aged populations. The major hallmarks of Alzheimer’s disease include deposition of extracellular amyloid senile plaques and intracellular neurofibrillary tangles in brain neuronal cells. Although there are classical therapeutic options available for the treatment of the diseases, however, they provide only a symptomatic relief and do not modify the molecular pathophysiological course of the disease. Recent research advances in Alzheimer’s disease have highlighted the potential role of anti-amyloid, anti-tau, and anti-inflammatory therapies. However, these therapies are still in different phases of pre-clinical/clinical development. In addition, drug repositioning/repurposing is another interesting and promising approach to explore rationalized options for the treatment of Alzheimer’s disease.This review discusses the different aspects of the pathophysiological mechanism involved in the progression of Alzheimer’s disease along with the limitations of current therapies. Furthermore, this review also highlights emerging investigational drugs along with recent drug repurposing approaches for Alzheimer’s disease.

Peptidyl-Prolyl Cis/Trans Isomerase Pin1 and Alzheimer's Disease.

Alzheimer’s disease (AD) is the most common cause of dementia with cognitive decline. The neuropathology of AD is characterized by intracellular aggregation of neurofibrillary tangles consisting of hyperphosphorylated tau and extracellular deposition of senile plaques composed of beta-amyloid peptides derived from amyloid precursor protein (APP). The peptidyl-prolyl cis/trans isomerase Pin1 binds to phosphorylated serine or threonine residues preceding proline and regulates the biological functions of its substrates. Although Pin1 is tightly regulated under physiological conditions, Pin1 deregulation in the brain contributes to the development of neurodegenerative diseases, including AD. In this review, we discuss the expression and regulatory mechanisms of Pin1 in AD. We also focus on the molecular mechanisms by which Pin1 controls two major proteins, tau and APP, after phosphorylation and their signaling cascades. Moreover, the major impact of Pin1 deregulation on the progression of AD in animal models is discussed. This information will lead to a better understanding of Pin1 signaling pathways in the brain and may provide therapeutic options for the treatment of AD.

Antibodies directed to the phospho-tau peptide (residues 111-137) dissociate tau oligomers and reduce the spatial memory deficits in non-transgenic tauopathy model rats

In dementia, Alzheimer’s disease (AD) is the most common type, characterized by the deposits of neurofibrillary tangles and senile plaques with concomitant deterioration in spatial memory and other cognitive functions. Till date, although no cure is available for AD, a few treatment options offer help in reducing the symptoms. In the present study, the sequence 111-137 in the distal N-terminal charge transition region of tau, harbouring the pathologically relevant phospho-serine (pSer 113) and phospho-threonine (pThr 123) (111TPpSLEDEAAGHVpTQARMVSKSKD GTGS137)was selected as a potential immunotherapeutic peptide. Polyclonal anti-peptide antibodies raised in rabbits effectively dissociated the oligomers/aggregates of recombinant human tau in vitro. Administration of affinity purified anti-peptide antibodies to the okadaic acid induced tauopathy model rats resulted in a significant progress in spatial memory functions in Barnes maze task with concomitant reduction in p-tau levels in the hippocampal homogenates. Thus, targeting the phospho-residue sequence 111-137 in tau may be therapeutically relevant for AD and other related tauopathies. These antibodies may also have a clinical value in terms of immunosassay development for quantitation of pathology associated pSer113 and pThr 123 in AD samples.

Antagonism of cysteinyl leukotrienes and their receptors as a neuroinflammatory target in Alzheimer's disease.

Alzheimer's disease is a complex multifaceted neurodegenerative disorder. It is characterized by the deposition of extracellular amyloid senile plaques and intracellular neurofibrillary tangles leading to progressive dementia and death in aged adult population. Recent emerging research has highlighted a potential pharmacological role of 5-lipoxyenase-cysteinyl leukotriene pathway in molecular pathogenesis of Alzheimer's disease. Although cysteinyl leukotrienes and their receptors have a major clinical role in chronic respiratory inflammation, their roles in chronic neuroinflammation in Alzheimer's disease need a detailed and careful exploration. This review article highlights a novel role of cysteinyl leukotrienes and their receptors in pathophysiology of Alzheimer's disease in order to understand the underlying molecular mechanism. In addition, it summarizes the recent advances in various pre-clinical and clinical strategies used to modulate this pathway for therapeutic targeting of Alzheimer's disease.

Effect of Zhenxin Xingshui Yizhi Fang on Aβ25-35 induced expression of related transporters in HBMEC cell model

Ethnopharmacological relevanceAβ (β-amyloid) deposition and abnormal transport were suggested to be risk factors for Alzheimer's disease (AD). Zhenxin Xingshui Yizhi Fang (XSF), an ancient prescription in traditional Chinese medicine, was first recorded in Qianjin Yifang for treating palpitation, hypnosia, amnesia. It is reported that XSF could improve mice learning memory ability, reduce the deposition of senile plaques in hippocampus of rat brain. In this study, the neuroprotective effect of XSF against Aβ25-35-induced apoptosis in cultured human brain microvascular endothelial cells (HBMEC) and its potential mechanism were investigated. Materials and methodsHBMEC cells were treated with Aβ25-35 to established neurotoxic cell model. After that, the cells were treated with 125, 250, 500 μg/mL XSF to observe the protective effect. The viability of HBMEC cells were evaluated by MTT assay, the Aβ25-35-induced apoptosis was characterized by Hoechst-33258 and the activity of cysteinyl aspartate specific proteinase-3. The expression level of Aβ1-42 in cells induced by Aβ25-35 was measured by human Aβ1-42 kit. Protein and mRNA expression levels of advanced glycation end products (RAGE), low density lipoprotein receptor-related protein 1 (LRP1), glucose transporter 1 and 3 (GLUT1 and GLUT3) were assayed by capillary electrophoresis immunoassay and quantitative real-time polymerase chain reaction analyses. ResultsIn Aβ25-35 induced neurotoxic cells, the percentage of apoptotic cells, the concentration of Aβ1-42 and CASPASE-3 activity, protein and mRNA expression levels of RAGE increased significantly, but that of LRP1, GLUT1 and GLUT3 significantly decreased. XSF could inhibit the apoptotic of cells, reduced the concentration of Aβ1-42 and CASPASE-3 expression, downregulate RAGE and upregulate LRP1, GLUT1 and GLUT3 expression. ConclusionThe results suggest that XSF can reduce the cytotoxicity of HBMEC induced by Aβ25-35, inhibit apoptosis, and regulate the transport of Aβ on BBB and energy metabolism disorder in HBMEC.

Liraglutide Protects Against Brain Amyloid-β1-42 Accumulation in Female Mice with Early Alzheimer's Disease-Like Pathology by Partially Rescuing Oxidative/Nitrosative Stress and Inflammation.

Alzheimer’s disease (AD) is the most common form of dementia worldwide, being characterized by the deposition of senile plaques, neurofibrillary tangles (enriched in the amyloid beta (Aβ) peptide and hyperphosphorylated tau (p-tau), respectively) and memory loss. Aging, type 2 diabetes (T2D) and female sex (especially after menopause) are risk factors for AD, but their crosslinking mechanisms remain unclear. Most clinical trials targeting AD neuropathology failed and it remains incurable. However, evidence suggests that effective anti-T2D drugs, such as the GLP-1 mimetic and neuroprotector liraglutide, can be also efficient against AD. Thus, we aimed to study the benefits of a peripheral liraglutide treatment in AD female mice. We used blood and brain cortical lysates from 10-month-old 3xTg-AD female mice, treated for 28 days with liraglutide (0.2 mg/kg, once/day) to evaluate parameters affected in AD (e.g., Aβ and p-tau, motor and cognitive function, glucose metabolism, inflammation and oxidative/nitrosative stress). Despite the limited signs of cognitive changes in mature female mice, liraglutide only reduced their cortical Aβ1–42 levels. Liraglutide partially attenuated brain estradiol and GLP-1 and activated PKA levels, oxidative/nitrosative stress and inflammation in these AD female mice. Our results support the earlier use of liraglutide as a potential preventive/therapeutic agent against the accumulation of the first neuropathological features of AD in females.

Qingxin Kaiqiao Recipe Improves Cognitive Performance, Inhibits Apoptosis, and Reduces Pathological Deposits in APP/PS1 Double Transgenic Mice via the PI3K/Akt Pathway.

The traditional Chinese medicine of Qingxin Kaiqiao Recipe (QKR) is effective in the treatment of Alzheimer's disease (AD). This study aims to investigate whether QKR improves the cognitive ability and takes neuroprotective effect on APP/PS1 double transgenic mice via the PI3K/Akt pathway. APP/PS1 double transgenic mice were randomly divided into a model, donepezil-treated, or QKR-treated group (L-QKR: 4.75 mg/kg/d, M-QKR: 9.5 mg/kg/d, and H-QKR: 19 mg/kg/d, respectively). Wild-type C57/BL6J mice were used as the control group. Morris water maze (MWM) was used to test the ability of spatial navigation and memorization; terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) assay was applied to test the apoptosis; amyloid protein granule deposition was detected via Methenamine silver staining; Western blot (WB) analysis, immunohistochemistry, and RT-PCR were applied to measure the expression of Aβ and corresponding indicators of the PI3K/Akt pathway. Compared with the model group, QKR significantly relieved the cognitive impairment, reduced the deposition of senile plaques, decreased the expression of GSK-3α and Aβ, and increased the expression of p-PI3K, p-Akt, and IDE. In addition, the number of TUNEL-positive cells decreased after treatment using QKR. The current study proved that QKR, especially at the high dose tested, exerted a protective effect on improving learning and memory, inhibiting apoptosis, and reducing the process of pathological degeneration in the hippocampus of AD mice.

Yeast beta-Glucan effects on gut microbiota for regulating insulin signaling system on alzheimer's disease

AbstractIntroduction:Alzheimer's disease (AD) is a progressive neurodegenerative disease for dementia in adults. The main pathological alterations are extracellular senile plaque deposits, intracellular neurofibrillary tangles and neuronal apoptosis. Recent researches indicated that T2D is closely with AD by insulin resistance in central nerves system progression. Nevertheless, the pathological mechanism remains unclear and treatment is limited. β-glucan extracted from yeast, as a dietary fiber with high bioactivity, edible, good taste and easy-obtainable, have been showed abilities such as anti-diabetic, anti-inflammatory and prebiotic. Based on this, β-glucan can reduce insulin resistance and maintain gut microbiota thereby alleviating lesions of early AD.Materials and Methods:In this study, we used 36 male wild-type C57BL/6J mice were divided to 3 groups (control (C) mice injected i.c.v. with 0.9% saline as a vehicle, mice injected i.c.v. with Aβ1–42 (Aβ1–42 group), mice injected with Aβ1–42 and soluble yeast β-glucan 100 mg/kg body weight by oral gavage daily (o.g.) for 5 wks (Aβ1–42 + Glu)). H&E method was detected for structure of hippocampus. Morris water maze test was performed to assess the cognitive performance of Aβ-infusion mice. The microbiota composition was analyzed by 16sRNA sequencing. The levels of inflammatory were measured in hippocampal and plasma by Meso-scale Discovery (MSD). Western blot was performed to detect the level of protein in insulin signaling pathway. One-way ANNOVA with Student-Newman-Keuls was applied for the data analysis through SPSS software version 22.0.Results:As demonstrated by H&E sections, β-glucan reduced neuron damage in AD mice hippocampus. Decreased the levels of Aβ and phosphorylation of Tau protein expression in hippocampus (P < 0.05) and ameliorated insulin resistance (p-IRS-1) in hippocampus (P < 0.05). According by results from MSD and Western-blot that showed TNF-α (P < 0.05), phosphorylated JNK (P < 0.01) and Tau were up-regulated in AD but β-glucan group decreased. In addition, the abundance of beneficial bacteria in β-glucan mice is increased (g_Alistipes, g_Rikeenella and g_Saccharibecteria genera incerae sedies).Discussion:Summary, this study illustrated that β-glucan regulated insulin signaling for ameliorating learning and memory deficit in AD. Due to β-glucan can not pass Blood-Brain-Barrier, we hypothesized that β-glucan could regulates gut microbiota by metabolites for ameliorating neuron damage. Our study provides new ideas for the prevention of AD.

In vitro pathological model of Alzheimer's disease based on neuronal network chip and its real-time dynamic analysis

Alzheimer's disease (AD) is a chronic central neurodegenerative disease. The pathological features of AD are the extracellular deposition of senile plaques formed by amyloid-β oligomers (AβOs) and the intracellular accumulation of neurofibrillary tangles formed by hyperphosphorylated tau protein. In this paper, an in vitro pathological model of AD based on neuronal network chip and its real-time dynamic analysis were presented. The hippocampal neuronal network was cultured on the microelectrode array (MEA) chip and induced by AβOs as an AD model in vitro to simultaneously record two firing patterns from the interneurons and pyramidal neurons. The spatial firing patterns mapping and cross-correlation between channels were performed to validate the degeneration of neuronal network connectivity. This biosensor enabled the detection of the AβOs toxicity responses, and the identification of connectivity and interactions between neuronal networks, which can be a novel technique in the research of AD pathological model in vitro.

Tiaoxin Recipe, a Chinese herbal formula, inhibits microRNA-34a expression in the APPswe/PS1ΔE9 mouse model of Alzheimer’s disease

ObjectiveTo investigate the effect and underlying mechanisms of Tiaoxin Recipe (a Chinese herbal formula) treatment on Alzheimer’s disease (AD). MethodsTwelve-week-old APPswe/PS1ΔE9 (APP/PS1) double transgenic mice were used as a model of AD-afflicted mice. One group of mice was treated with Tiaoxin Recipe by gastrogavage for 12 weeks, while two other groups were given intraperitoneal injections of nicotinamide adenine dinucleotide or FK866 for 4 weeks. Morris water maze and thioflavin S staining tests were performed to evaluate cognitive impairment and amyloid plaque deposition, respectively. Serum amyloid-β1-42 (Aβ1-42) content was detected using an enzyme-linked immunosorbent assay, and quantitative reverse transcription-polymerase chain reaction was performed to examine the expression levels of microRNA-34a (miR-34a) in cortex and hippocampus samples of the study mice. ResultsCompared with the normal control group, the memory and learning abilities of the APP/PS1 model group were found to be impaired (P < 0.01), as shown by the increased levels of senile plaque deposition in cortex and hippocampus (P < 0.01), miR-34a expression (P < 0.01) and serum Aβ1-42 content (P < 0.01). Treatment with Tiaoxin Recipe significantly reduced memory impairment (P < 0.01) by reducing amyloid plaque accumulation in cortex and hippocampus (P < 0.01), miR-34a expression (P < 0.01) and serum Aβ1-42 content (P < 0.01) in APP/PS1 mice. ConclusionTiaoxin Recipe is a viable complementary or alternative therapeutic treatment that is capable of delaying the development of early-stage AD by inhibiting the expression of miR-34a.

Phenothiazine-based theranostic compounds for in vivo near-infared fluorescence imaging of β-amyloid plaques and inhibition of Aβ aggregation

A global burden of Alzheimer's disease (AD) has been growing over last decades. Evidence indicates that β-amyloid (Aβ) production and senile plaque deposition in the brain is causative in the onset of AD pathogenesis. It appears much earlier than cognitive decline and plays a key role in initiating and developing AD neuropathology. As such, there is an intense passion with discovering theranostic agents which make a significant impact in diagnostic and therapy. Herein, we report an investigation of novel phenothiazine-based compounds as promising potential theranostic agents for AD. Remarkably, they have exhibited a high binding affinity toward Aβ aggregates, a good biostability and a strong increase in their fluorescence intensity with blue shift when interacting with Aβ aggregates. Furthermore, they have been simultaneously applied to perform NIR in vivo imaging of β-amyloid plaques in double transgenic AD mouse model, to prevent self-aggregation of Aβ monomer from forming toxic oligmers and to reduce Aβ-induced toxicity of human neuroblastoma cells (SH-SY5Y).

α7 nicotinic ACh receptors are necessary for memory recovery and neuroprotection promoted by attention training in amyloid-β-infused mice.

Attention training reverses the neurodegeneration and memory loss promoted by infusion of amyloid-β (Aβ) peptide in rats and increases the density of α7 nicotinic ACh receptors (α7nAChRs) in brain areas related to memory. Hence, we aimed to assess the role of α7nAChRs in the memory recovery promoted by attention training. C57Bl/6 mice were chronically infused with Aβ, Aβ plus the α7 antagonist methyllycaconitine (MLA), or MLA alone. Control animals were infused with vehicle. Animals were subjected weekly to the active avoidance shuttle box for 4weeks (attention training). The brain and serum were collected for biochemical and histological analysis. Aβ caused cognitive impairment, which was reversed by the weekly training, whereas Aβ+MLA also promoted memory loss but with no reversal with weekly training. MLA alone also promoted memory loss but with only partial reversal with the training. Animals infused with Aβ alone showed senile plaques in hippocampus, no change in BDNF levels in cortex, hippocampus, and serum, but increased AChE activity in cortex and hippocampus. Co-treatment with MLA increased AChE activity and senile plaque deposition in hippocampus as well as reducing BDNF in hippocampus and serum, suggesting a lack of α7nAChR function leads to a loss of neuroprotection mechanisms. The α7nAChR has a determinant role in memory recovery and brain resilience in the presence of neurodegeneration promoted by Aβ peptide. These data support further studies concerning these receptors as pharmacological targets for future therapies.

Metal Ions in Alzheimer's Disease: A Key Role or Not?

Despite tremendous research efforts in universities and pharmaceutical companies, effective drugs are still lacking for the treatment of Alzheimer's disease (AD). The biochemical mechanisms of this devastating neurodegenerative disease have not yet been clearly understood. Besides a small percentage of cases with early onset disease having a genetic origin (<5%, familial AD), most cases develop in the elderly as a sporadic form due to multiple and complex parameters of aging. Consequently, AD is spreading in all countries with a long life expectancy. AD is characterized by deposition of senile plaques made of β-amyloid proteins (Aβ) and by hyperphosphorylation of tau proteins, which have been considered as the main drug targets up to now. However, antibodies targeting amyloid aggregates, as well as enzyme inhibitors aiming to modify the amyloid precursor protein processing, have failed to improve cognition in clinical trials. Thus, to set up effective drugs, it is urgent to enlarge the panel of drug targets. Evidence of the link between AD and redox metal dysregulation has also been supported by post-mortem analyses of amyloid plaques, which revealed accumulation of copper, iron, and zinc by 5.7, 2.8, and 3.1 times, respectively, the levels observed in normal brains. Copper-amyloid complexes, in the presence of endogenous reductants, are able to catalyze the reduction of dioxygen and to produce reduced, reactive oxygen species (ROS), leading to neuron death. The possibility of using metal chelators to regenerate normal trafficking of metal ions has been considered as a promising strategy in order to reduce the redox stress lethal for neurons. However, most attempts to use metal chelators as therapeutic agents have been limited to existing molecules available from the shelves. Very few chelators have resulted from a rational design aiming to create drugs with a safety profile and able to cross the blood-brain barrier after an oral administration. In the human body, metals are handled by a sophisticated protein network to strictly control their transport and reactivity. Abnormal concentrations of certain metals may lead to pathological events due to misaccumulation and irregular reactivity. Consequently, therapeutic attempts to restore metal homeostasis should carefully take into account the coordination chemistry specificities of the concerned redox-active metal ions. This Account is focused on the role of the main biologically redox-active transition metals, iron and copper. For iron, the recent debate on the possible role of magnetite in AD pathogenesis is presented. The section devoted to copper is focused on the design of specific copper chelators as drug candidates able to regulate copper homeostasis and to reduce the oxidative damage responsible for the neuron death observed in AD brains. A short survey on non-redox-active metal ions is also included at the beginning, such as aluminum and its controversial role in AD and zinc which is a key metal ion in the brain.

In Silico Approach for Designing Potent Neuroprotective Hexapeptide.

Alzheimer's disease (AD) is a constantly recurring neurodegenerative disease that deteriorates over a period of time. In this pathology, connections between neurons become extremely damaged due to the deposition of senile plaques in the membrane region, which results in abnormal signal transduction processes. Also, the intracellular microtubule networks are disrupted in the hyperphosphorylated tau cascade of AD. Therefore, design and development of potent neuroprotective molecules that can instantaneously target multiple facets of AD pathogenesis are greatly needed to tackle this unmet medical need. Here, we have implemented a pharmacophore based in silico analysis of various neuroprotective peptides known for neurotherapeutic application in AD. Fascinatingly, we have identified an active core of these peptides and designed a library of hexapeptides. We observed that peptide "LETVNQ" (LE6) has shown significant protection ability against degeneration of neurons. Experimental evidence suggests that this peptide immensely reduced the aggregation rate of amyloid-β (Aβ) and helped in microtubule polymerization. Intriguingly, this newly designed peptide does not have any cytotoxicity toward differentiated PC12 neurons; rather it helps in neurite outgrowth. Further, LE6 helps to maintain the complex microtubule network in cells by promoting the polymerization rate of intracellular microtubules and mediates excellent protection of neurons even after removal of nerve growth factor (NGF). Finally, we observed that this LE6 peptide has substantial stability under physiological conditions and helps to retain healthy morphology of primary rat cortical neurons. This excellent piece of work identifies a potent hexapeptide, which has exceptional ability to protect neurons as well as microtubule from degeneration and may become potent therapeutics against AD pathogenesis in the future.

Gemfibrozil, a Lipid-Lowering Drug, Lowers Amyloid Plaque Pathology and Enhances Memory in a Mouse Model of Alzheimer's Disease via Peroxisome Proliferator-Activated Receptor α.

Deposition of extracellular senile plaques containing amyloid-β is one of the major neuropathological characteristics of Alzheimer’s disease (AD). Therefore, targeting amyloid-β dyshomeostasis is an important therapeutic strategy for treatment of AD. In this study, we demonstrate that gemfibrozil, an FDA-approved drug for hyperlipidemia, can lower the amyloid plaque burden in the hippocampus and cortex of the 5XFAD model of AD. Additionally, gemfibrozil reduced microgliosis and astrogliosis associated with plaque in these mice. Administration of gemfibrozil also improved spatial learning and memory of the 5XFAD mice. Finally, we delineate that gemfibrozil requires the transcription factor peroxisome proliferator-activated receptor alpha (PPARα) to exhibit its amyloid lowering and memory enhancing effects in 5XFAD mice. These results highlight a new therapeutic property of gemfibrozil and suggest that this drug may be repurposed for treatment of AD.

Alteration of the Wnt/GSK3β/β‑catenin signalling pathway by rapamycin ameliorates pathology in an Alzheimer's disease model.

The abnormal activation of glycogen synthase kinase 3β (GSK3β) is one of the mechanisms involved in the pathogenesis of Alzheimer's disease (AD), which results in amyloid β‑peptide (Aβ) plaque overproduction, Tau hyperphosphorylation and neuronal loss. A number of studies have reported that the activation of the mammalian target of rapamycin (mTOR) contributes to the generation and deposition of Aβ, as well as to the formation of neurofibrillary tangles (NFTs) by inhibiting autophagy. GSK3β is also involved in the mTOR signalling pathway. However, whether the inhibition of the activation of mTOR via the regulation of the function of GSK3β affects the pathology of AD remains unclear. In this study, we intraperitoneally injected amyloid precursor protein (APP)/presenilin‑1 (PS1) transgenic mice with rapamycin, a known activator of autophagy that inhibits mTOR. Our results revealed that rapamycin treatment decreased senile plaque deposition by reducing APP generation, and downregulating β‑ and γ‑secretase activity. Rapamycin also increased Aβ clearance by promoting autophagy and reduced Tau hyperphosphorylation by upregulating the levels of insulin‑degrading enzyme. Additionally, rapamycin markedly promoted the proliferation of differentiated SH‑SY5Y cells stably transfected with the APPswe gene and prevented neuronal loss in the brains of mice in a model of AD. Moreover, rapamycin induced autophagy and promoted autolysosome degradation. In this study, we provide evidence that rapamycin inhibits GSK3β activation and elevates β‑catenin expression by improving the Wnt3a expression levels, which facilitates the amelioration of AD pathology. On the whole, our findings indicate that rapamycin inhibits the activation of mTOR and alters the Wnt/GSK3β/β‑catenin signalling pathway; thus, it may serve as a therapeutic target in the treatment of AD.