Accumulation Of Β-amyloid Protein Research Articles

Bioactive human Alzheimer brain soluble Aβ: pathophysiology and therapeutic opportunities.

The accumulation of amyloid-β protein (Aβ) plays an early role in the pathogenesis of Alzheimer's disease (AD). The precise mechanism of how Aβ accumulation leads to synaptic dysfunction and cognitive impairment remains unclear but is likely due to small soluble oligomers of Aβ (oAβ). Most studies have used chemical synthetic or cell-secreted Aβ oligomers to study their pathogenic mechanisms, but the Aβ derived from human AD brain tissue is less well characterized. Here we review updated knowledge on the extraction and characterization of bioactive human AD brain oAβ and the mechanisms by which they cause hippocampal synaptic dysfunction. Human AD brain-derived oAβ can impair hippocampal long-term potentiation (LTP) and enhance long-term depression (LTD). Many studies suggest that oAβ may directly disrupt neuronal NMDA receptors, AMPA receptors and metabotropic glutamate receptors (mGluRs). oAβ also impairs astrocytic synaptic functions, including glutamate uptake, D-serine release, and NMDA receptor function. We also discuss oAβ-induced neuronal hyperexcitation. These results may suggest a multi-target approach for the treatment of AD, including both oAβ neutralization and reversal of glutamate-mediated excitotoxicity.

Small Oligomers of Aβ42 Protein in the Bulk Solution with AlphaFold2.

Aggregation of amyloid-β (Aβ42) protein is one hallmark of Alzheimer's disease, and the conformations of the smallest Aβ42 oligomers are largely unknown. Here, we explore the application of the deep learning AlphaFold2 method to the structure determination of Aβ42 monomers up to hexamers. The results shed light on the early Aβ42 aggregation steps in the bulk solution.

A Synergistic Combination of DHA, Luteolin, and Urolithin A Against Alzheimer's Disease.

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and the most common form of dementia worldwide. The classical AD brain is characterized by extracellular deposition of amyloid-β (Aβ) protein aggregates as senile plaques and intracellular neurofibrillary tangles (NFTs), composed of hyper-phosphorylated forms of the microtubule-associated protein Tau. There has been limited success in clinical trials for some proposed therapies for AD, so attention has been drawn toward using alternative approaches, including prevention strategies. As a result, nutraceuticals have become attractive compounds for their potential neuroprotective capabilities. The objective of the present study was to derive a synergistic nutraceutical combination in vitro that may act as a potential preventative therapy for AD. The compounds of interest were docosahexaenoic acid (DHA), luteolin (LUT), and urolithin A (UA). The cell viability and cytotoxicity assays MTS and LDH were used to evaluate the compounds individually and in two-compound combinations, for their ability to inhibit Aβ1–42-induced toxicity in human neuroblastoma BE(2)-M17 cells. The LDH-derived% protection values were used in the program CompuSyn v.1.0 to calculate the combination index (CI) of the two-compound combinations. The software-predicted potentially synergistic (CI < 1) two-compound combinations were validated using CellTiter Glo assay. Finally, a three-compound combination was predicted (D5L5U5) and shown to be the most effective at inhibiting Aβ1–42-induced toxicity. The synergistic combination, D5L5U5 warrants further research for its mechanism of action; however, it can serve as a basis to develop an advanced functional food for the prevention or co-treatment of AD.

Tolcapone Derivative (Tol-D) Inhibits Aβ42 Fibrillogenesis and Ameliorates Aβ42-Induced Cytotoxicity and Cognitive Impairment.

Abnormal aggregation and subsequent fibrillogenesis of amyloid-β protein (Aβ) can cause Alzheimer's disease (AD). Thus, the discovery of effective drugs that inhibit Aβ fibrillogenesis in the brain is important for the treatment of AD. Our previous study has proven that tolcapone inhibits Aβ fibrillogenesis and alleviates its cytotoxicity based on systematic in vitro and in vivo experiments. However, the severe hepatotoxicity of tolcapone seriously limits its further potential application in the treatment of AD. Herein, an inhibitory effect of a low-toxicity tolcapone derivative (Tol-D) on Aβ fibrillogenesis was explored. Based on the thioflavin T fluorescence data, Tol-D inhibited Aβ fibrillogenesis, and the inhibitory capacity increased with the increase of its concentrations with an IC50 of ∼8.99 μM. The results of cytotoxicity showed that Tol-D greatly reduced the cytotoxicity induced by Aβ42 fibrillogenesis. Moreover, Tol-D significantly alleviated Aβ deposits and extended the lifespan of nematodes in transgenic Caenorhabditis elegans models. Finally, Tol-D significantly relieved Aβ-induced cognitive dysfunction in mice experiments. Overall, the above experimental results indicated that Tol-D is a novel candidate therapeutic compound for the treatment of AD.

Callistephin inhibits amyloid-β protein aggregation and determined cytotoxicity against cerebrovascular smooth muscle cells as an in vitro model of cerebral amyloid angiopathy

It has been indicated that amyloid β (Aβ) plaques can be accumulated within the basement membranes of cerebrovascular smooth muscle cells (CVSMCs) and stimulate the induction of cerebral amyloid angiopathy (CAA). However, the exact mechanism(s) of which small molecules including callistephin mitigate the formation of Aβ aggregation and associated CAA is not well-understood. Therefore, in the present study, Aβ 1–42 samples in the aggregation buffer were co-incubated for 36 h without or with of callistephin and the protein aggregation features along with the associated cytotoxicity against CVSMCs as the core components of cerebral arterial wall were explored by different biochemical and cellular methods. Fluorescence (ThT, Nile red) and CD techniques indicated the inhibition of Aβ 1–42 fibrillization in the presence of callistephin. Cellular assays revealed that cytotoxicity of Aβ 1–42 samples aged in the aggregation buffer with callistephin was much less against CVSMCs than Aβ 1–42 amyloid alone through regulation of membrane leakage and downregulation of TNF-α and IL-6 at protein level. In conclusion, these data may provide useful information about the possible mechanisms by which callistephin can show its protective effect against CAA.

Endothelial Progenitor Cells and Vascular Alterations in Alzheimer's Disease.

Alzheimer’s disease (AD) is a neurodegenerative disease representing the most common type of dementia worldwide. The early diagnosis of AD is very difficult to achieve due to its complexity and the practically unknown etiology. Therefore, this is one of the greatest challenges in the field in order to develop an accurate therapy. Within the different etiological hypotheses proposed for AD, we will focus on the two-hit vascular hypothesis and vascular alterations occurring in the disease. According to this hypothesis, the accumulation of β-amyloid protein in the brain starts as a consequence of damage in the cerebral vasculature. Given that there are several vascular and angiogenic alterations in AD, and that endothelial progenitor cells (EPCs) play a key role in endothelial repair processes, the study of EPCs in AD may be relevant to the disease etiology and perhaps a biomarker and/or therapeutic target. This review focuses on the involvement of endothelial dysfunction in the onset and progression of AD with special emphasis on EPCs as a biomarker and potential therapeutic target.

Inactivation of seeding activity of amyloid β-protein aggregates in vitro.

Our study demonstrates that autoclaving (AC) decreases beta (β)-sheet-rich structures in amyloid β-protein (Aβ) aggregates, which inactivate Aβ seeding activity in vitro. Conformational changes that reduce β-sheet-rich structures would be important for understanding the molecular mechanisms underlying the inactivation of seeding activity of Aβ aggregates. Our in vitro study would contribute to the establishment of the inactivation methods for Aβ aggregates to prevent the propagation of Aβ pathology among individuals.

Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis.

Alzheimer's disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-β (Aβ) protein into amyloid plaques in patient brains. Mutations in presenilin (PS) lead to abnormal generation of Aβ, which is the major cause of familial AD (FAD), and apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) onset. However, whether dysfunction of PS is involved in the pathogenesis of SAD is largely unknown. We found that ApoE secretion was completely abolished in PS-deficient cells and markedly decreased by inhibition of γ-secretase activity. Blockade of γ-secretase activity by a γ-secretase inhibitor, DAPT, decreased ApoE secretion, suggesting an important role of γ-secretase activity in ApoE secretion. Reduced ApoE secretion is also observed in nicastrin-deficient cells with reduced γ-secretase activity. PS deficiency enhanced nuclear translocation of ApoE and binding of ApoE to importin α4, a nuclear transport receptor. Moreover, the expression of PS mutants in PS-deficient cells suppressed the restoration effects on ApoE secretion compared with the expression of wild-type PS. Plasma ApoE levels were lower in FAD patients carrying PS1 mutations compared with normal control subjects. Our findings suggest a novel role of PS contributing to the pathogenesis of SAD by regulating ApoE secretion.SIGNIFICANCE STATEMENT Familial AD (FAD) typically results from mutations in the genes encoding amyloid precursor protein, presenilin 1 (PS1), or PS2. Many PS mutants have been found to exert impaired γ-secretase activity and increased amyloid-β 42 (Aβ42)/Aβ40 ratio, which induce early amyloid deposition and FAD. On the other hand, apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) and contributes to AD pathogenesis because it has reduced Aβ clearance capability compared with ApoE3 and ApoE2. FAD and SAD have long been considered to be caused by these two independent mechanisms; however, for the first time, we demonstrated that PS is essential for ApoE secretion and PS mutants affected ApoE secretion in vitro and in human samples, suggesting a novel mechanism by which PS is also involved in SAD pathogenesis.

Simultaneous visualization and quantification of copper (II) ions in Alzheimer's disease by a near-infrared fluorescence probe

The abnormal accumulation of copper ions (Cu2+) is considered to be one of the pathological factors of Alzheimer's disease (AD), but the internal relationship between Cu2+ and AD progression is still not fully clear. In this work, a sensitive and selective near-infrared fluorescent copper ion probe (DDP-Cu) was designed for quantification and visualization of Cu2+ level in lysates, living cells, living zebrafish and brain tissues of drosophila and mice with AD. By using this probe, we demonstrated that the content of Cu2+ in the brains of AD mice and drosophila enhanced nearly 3.5-fold and 4-fold than that of normal mice and drosophila, respectively. More importantly, pathogenesis analysis revealed that elevated Cu2+ led to changes in factors closely associated with AD, such as the increasing of reactive oxygen species(ROS), the aggregation of amyloid-β protein (Aβ) and nerve cell cytotoxicity. These findings could promote the understanding of the roles between Cu2+ and AD.

Inhalational Anesthetics Do Not Deteriorate Amyloid-β-Derived Pathophysiology in Alzheimer's Disease: Investigations on the Molecular, Neuronal, and Behavioral Level.

Studies suggest that general anesthetics like isoflurane and sevoflurane may aggravate Alzheimer's disease (AD) neuropathogenesis, e.g., increased amyloid-β (Aβ) protein aggregation resulting in synaptotoxicity and cognitive dysfunction. Other studies showed neuroprotective effects, e.g., with xenon. In the present study, we want to detail the interactions of inhalational anesthetics with Aβ-derived pathology. We hypothesize xenon-mediated beneficial mechanisms regarding Aβ oligomerization and Aβ-mediated neurotoxicity on processes related to cognition. Oligomerization of Aβ1-42 in the presence of anesthetics has been analyzed by means of TR-FRET and silver staining. For monitoring changes in neuronal plasticity due to anesthetics and Aβ1-42, Aβ1-40, pyroglutamate-modified amyloid-(AβpE3), and nitrated Aβ (3NTyrAβ), we quantified long-term potentiation (LTP) and spine density. We analyzed network activity in the hippocampus via voltage-sensitive dye imaging (VSDI) and cognitive performance and Aβ plaque burden in transgenic AD mice (ArcAβ) after anesthesia. Whereas isoflurane and sevoflurane did not affect Aβ1-42 aggregation, xenon alleviated the propensity for aggregation and partially reversed AβpE3 induced synaptotoxic effects on LTP. Xenon and sevoflurane reversed Aβ1-42-induced spine density attenuation. In the presence of Aβ1-40 and AβpE3, anesthetic-induced depression of VSDI-monitored signaling recovered after xenon, but not isoflurane and sevoflurane removal. In slices pretreated with Aβ1-42 or 3NTyrAβ, activity did not recover after washout. Cognitive performance and plaque burden were unaffected after anesthetizing WT and ArcAβ mice. None of the anesthetics aggravated Aβ-derived AD pathology in vivo. However, Aβ and anesthetics affected neuronal activity in vitro, whereby xenon showed beneficial effects on Aβ1-42 aggregation, LTP, and spine density.

A dual-screening electrochemiluminescent aptasensor based on a mesoporous silica nano-sieve for specific detection of amyloid-β monomer

Amyloid β-protein (Aβ) aggregation in the brain is a closely related symptom of Alzheimer’s disease (AD), while Aβ in blood might be a more accessible peripheral biomarker to predict AD much earlier due to its abnormal fluctuation. However, when developing an aptasensor for Aβ detection, the specificity of the sensor will be impaired by Aβ aggregates such as Aβ oligomers or fibers because they have the same unit of recognition. Herein, a novel dual-screening sensing strategy based on specific recognition by aptamers and nano-sieving by a mesoporous silica membrane (MSM) with electrochemiluminescence (ECL) as the output signal is reported, in which the MSM achieves a size-screening effect to eliminate the influence of those macromolecules, assisting the specificity screening of the aptamer. The ECL signal is determined by the steric hindrance of the specifically captured Aβ on the aptamer in the nanochannels of the MSM towards the probe (luminol), affording a highly sensitive and specific detection ability for Aβ in complex matrices. In general, this work develops an ECL sensor that integrates aptamer recognition with size-selective separation for blood Aβ detection, which positively helps to monitor the occurrence and development of AD.

Medium-Chain Length Fatty Acids Enhance Aβ Degradation by Affecting Insulin-Degrading Enzyme.

The accumulation of amyloid β-protein (Aβ) is one of the major pathological hallmarks of Alzheimer’s disease. Insulin-degrading enzyme (IDE), a zinc-metalloprotease, is a key enzyme involved in Aβ degradation, which, in addition to Aβ production, is critical for Aβ homeostasis. Here, we demonstrate that saturated medium-chain fatty acids (MCFAs) increase total Aβ degradation whereas longer saturated fatty acids result in an inhibition of its degradation, an effect which could not be detected in IDE knock-down cells. Further analysis of the underlying molecular mechanism revealed that MCFAs result in an increased exosomal IDE secretion, leading to an elevated extracellular and a decreased intracellular IDE level whereas gene expression of IDE was unaffected in dependence of the chain length. Additionally, MCFAs directly elevated the enzyme activity of recombinant IDE, while longer-chain length fatty acids resulted in an inhibited IDE activity. The effect of MCFAs on IDE activity could be confirmed in mice fed with a MCFA-enriched diet, revealing an increased IDE activity in serum. Our data underline that not only polyunsaturated fatty acids such as docosahexaenoic acid (DHA), but also short-chain fatty acids, highly enriched, for example in coconut oil, might be beneficial in preventing or treating Alzheimer’s disease.

Gut Microbiota and Alzheimer's Disease: Pathophysiology and Therapeutic Perspectives.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly and is characterized by a progressive decline in cognitive function. Amyloid-β protein accumulation is believed to be the key pathological hallmark of AD. Increasing evidence has shown that the gut microbiota has a role in brain function and host behaviors. The gut microbiota regulates the bidirectional interactions between the gut and brain through neural, endocrine, and immune pathways. With increasing age, the gut microbiota diversity decreases, and the dominant bacteria change, which is closely related to systemic inflammation and health status. Dysbiosis of the gut microbiota is related to cognitive impairment and neurodegenerative diseases. The purpose of this review is to discuss the impacts of the gut microbiota on brain function and the development of AD. It is a feasible target for therapeutic invention. Modulating the composition of the gut microbiota through diet, physical activity or probiotic/prebiotic supplements can provide new prevention and treatment options for AD.

Nano-Infrared Imaging of Primary Neurons

Alzheimer’s disease (AD) accounts for about 70% of neurodegenerative diseases and is a cause of cognitive decline and death for one-third of seniors. AD is currently underdiagnosed, and it cannot be effectively prevented. Aggregation of amyloid-β (Aβ) proteins has been linked to the development of AD, and it has been established that, under pathological conditions, Aβ proteins undergo structural changes to form β-sheet structures that are considered neurotoxic. Numerous intensive in vitro studies have provided detailed information about amyloid polymorphs; however, little is known on how amyloid β-sheet-enriched aggregates can cause neurotoxicity in relevant settings. We used scattering-type scanning near-field optical microscopy (s-SNOM) to study amyloid structures at the nanoscale, in individual neurons. Specifically, we show that in well-validated systems, s-SNOM can detect amyloid β-sheet structures with nanometer spatial resolution in individual neurons. This is a proof-of-concept study to demonstrate that s-SNOM can be used to detect Aβ-sheet structures on cell surfaces at the nanoscale. Furthermore, this study is intended to raise neurobiologists’ awareness of the potential of s-SNOM as a tool for analyzing amyloid β-sheet structures at the nanoscale in neurons without the need for immunolabeling.

Three-dimensional-engineered bioprinted in vitro human neural stem cell self-assembling culture model constructs of Alzheimer's disease

The pathogenic cascade of Alzheimer's disease (AD) characterized by amyloid-β protein accumulation is still poorly understood, partially owing to the limitations of relevant models without in vivo neural tissue microenvironment to recapitulate cell–cell interactions. To better mimic neural tissue microenvironment, three-dimensional (3D) core-shell AD model constructs containing human neural progenitor cells (NSCs) with 2% matrigel as core bioink and 2% alginate as shell bioink have been bioprinted by a co-axial bioprinter, with a suitable shell thickness for nutrient exchange and barrier-free cell interaction cores. These constructs exhibit cell self-clustering and -assembling properties and engineered reproducibility with long-term cell viability and self-renewal, and a higher differentiation level compared to 2D and 3D MIX models. The different effects of 3D bioprinted, 2D, and MIX microenvironments on the growth of NSCs are mainly related to biosynthesis of amino acids and glyoxylate and dicarboxylate metabolism on day 2 and ribosome, biosynthesis of amino acids and proteasome on day 14. Particularly, the model constructs demonstrated Aβ aggregation and higher expression of Aβ and tau isoform genes compared to 2D and MIX controls. AD model constructs will provide a promising strategy to facilitate the development of a 3D in vitro AD model for neurodegeneration research.

Green Tea Polyphenol Epigallocatechin-Gallate in Amyloid Aggregation and Neurodegenerative Diseases.

The accumulation of protein aggregates in human tissues is a hallmark of more than 40 diseases called amyloidoses. In seven of these disorders, the aggregation is associated with neurodegenerative processes in the central nervous system such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). The aggregation occurs when certain soluble proteins lose their physiological function and become toxic amyloid species. The amyloid assembly consists of protein filament interactions, which can form fibrillar structures rich in β-sheets. Despite the frequent incidence of these diseases among the elderly, the available treatments are limited and at best palliative, and new therapeutic approaches are needed. Among the many natural compounds that have been evaluated for their ability to prevent or delay the amyloidogenic process is epigallocatechin-3-gallate (EGCG), an abundant and potent polyphenolic molecule present in green tea that has extensive biological activity. There is evidence for EGCG’s ability to inhibit the aggregation of α-synuclein, amyloid-β, and huntingtin proteins, respectively associated with PD, AD, and HD. It prevents fibrillogenesis (in vitro and in vivo), reduces amyloid cytotoxicity, and remodels fibrils to form non-toxic amorphous species that lack seed propagation. Although it is an antioxidant, EGCG in an oxidized state can promote fibrils’ remodeling through formation of Schiff bases and crosslinking the fibrils. Moreover, microparticles to drug delivery were synthesized from oxidized EGCG and loaded with a second anti-amyloidogenic molecule, obtaining a synergistic therapeutic effect. Here, we describe several pre-clinical and clinical studies involving EGCG and neurodegenerative diseases and their related mechanisms.

Indomethacin Disrupts the Formation of β-Amyloid Plaques via an α2-Macroglobulin-Activating lrp1-Dependent Mechanism.

Epidemiological studies have implied that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows the development and progression of Alzheimer’s disease (AD). However, the underlying mechanisms are notably understudied. Using a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) (APP/PS1) expressing transgenic (Tg) mice and neuroblastoma (N) 2a cells as in vivo and in vitro models, we revealed the mechanisms of indomethacin in ameliorating the cognitive decline of AD. By screening AD-associated genes, we observed that a marked increase in the expression of α2-macroglobulin (A2M) was markedly induced after treatment with indomethacin. Mechanistically, upregulation of A2M was caused by the inhibition of cyclooxygenase-2 (COX-2) and lipocalin-type prostaglandin D synthase (L-PGDS), which are responsible for the synthesis of prostaglandin (PG)H2 and PGD2, respectively. The reduction in PGD2 levels induced by indomethacin alleviated the suppression of A2M expression through a PGD2 receptor 2 (CRTH2)-dependent mechanism. Highly activated A2M not only disrupted the production and aggregation of β-amyloid protein (Aβ) but also induced Aβ efflux from the brain. More interestingly, indomethacin decreased the degradation of the A2M receptor, low-density lipoprotein receptor-related protein 1 (LRP1), which facilitated the brain efflux of Aβ. Through the aforementioned mechanisms, indomethacin ameliorated cognitive decline in APP/PS1 Tg mice by decreasing Aβ production and clearing Aβ from the brains of AD mice.

Insulin Resistance Exacerbates Alzheimer Disease via Multiple Mechanisms.

Alzheimer disease (AD) is a chronic neurodegenerative disease that accounts for 60–70% of dementia and is the sixth leading cause of death in the United States. The pathogenesis of this debilitating disorder is still not completely understood. New insights into the pathogenesis of AD are needed in order to develop novel pharmacologic approaches. In recent years, numerous studies have shown that insulin resistance plays a significant role in the development of AD. Over 80% of patients with AD have type II diabetes (T2DM) or abnormal serum glucose, suggesting that the pathogenic mechanisms of insulin resistance and AD likely overlap. Insulin resistance increases neuroinflammation, which promotes both amyloid β-protein deposition and aberrant tau phosphorylation. By increasing production of reactive oxygen species, insulin resistance triggers amyloid β-protein accumulation. Oxidative stress associated with insulin resistance also dysregulates glycogen synthase kinase 3-β (GSK-3β), which leads to increased tau phosphorylation. Both insulin and amyloid β-protein are metabolized by insulin degrading enzyme (IDE). Defects in this enzyme are the basis for a strong association between T2DM and AD. This review highlights multiple pathogenic mechanisms induced by insulin resistance that are implicated in AD. Several pharmacologic approaches to AD associated with insulin resistance are presented.

RRY Inhibits Amyloid-β1-42 Peptide Aggregation and Neurotoxicity.

Background:Current understanding of amyloid-β protein (Aβ) aggregation and toxicity provides an extensive list of drugs for treating Alzheimer’s disease (AD); however, one of the most promising strategies for its treatment has been tri-peptides.Objective:The aim of this study is to examine those tri-peptides, such as Arg-Arg-Try (RRY), which have the potential of Aβ1–42 aggregating inhibition and Aβ clearance.Methods:In the present study, in silico, in vitro, and in vivo studies were integrated for screening tri-peptides binding to Aβ, then evaluating its inhibition of aggregation of Aβ, and finally its rescuing cognitive deficit.Results:In the in silico simulations, molecular docking and molecular dynamics determined that seven top-ranking tri-peptides could bind to Aβ1–42 and form stable complexes. Circular dichroism, ThT assay, and transmission electron microscope indicated the seven tri-peptides might inhibit the aggregation of Aβ1–42 in vitro. In the in vivo studies, Morris water maze, ELISA, and Diolistic staining were used, and data showed that RRY was capable of rescuing the Aβ1–42-induced cognitive deficit, reducing the Aβ1–42 load and increasing the dendritic spines in the transgenic mouse model.Conclusion:Such converging outcomes from three consecutive studies lead us to conclude that RRY is a preferred inhibitor of Aβ1–42 aggregation and treatment for Aβ-induced cognitive deficit.

Elevating the Levels of Calcium Ions Exacerbate Alzheimer's Disease via Inducing the Production and Aggregation of β-Amyloid Protein and Phosphorylated Tau.

Alzheimer’s disease (AD) is a neurodegenerative disease with a high incidence rate. The main pathological features of AD are β-amyloid plaques (APs), which are formed by β-amyloid protein (Aβ) deposition, and neurofibrillary tangles (NFTs), which are formed by the excessive phosphorylation of the tau protein. Although a series of studies have shown that the accumulation of metal ions, including calcium ions (Ca2+), can promote the formation of APs and NFTs, there is no systematic review of the mechanisms by which Ca2+ affects the development and progression of AD. In view of this, the current review summarizes the mechanisms by which Ca2+ is transported into and out of cells and organelles, such as the cell, endoplasmic reticulum, mitochondrial and lysosomal membranes to affect the balance of intracellular Ca2+ levels. In addition, dyshomeostasis of Ca2+ plays an important role in modulating the pathogenesis of AD by influencing the production and aggregation of Aβ peptides and tau protein phosphorylation and the ways that disrupting the metabolic balance of Ca2+ can affect the learning ability and memory of people with AD. In addition, the effects of these mechanisms on the synaptic plasticity are also discussed. Finally, the molecular network through which Ca2+ regulates the pathogenesis of AD is introduced, providing a theoretical basis for improving the clinical treatment of AD.