Formation Of Senile Plaques Research Articles

Modeling the short time-scale dynamics of β-amyloid–neuron interactions

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the formation of senile plaques and neurofibrillary tangles. The primary protein components of these two histopathological features, β-amyloid peptide (Aβ) and tau, respectively, have been implicated in neuronal death. Despite extensive research into the disease etiology, its underlying molecular processes remain unknown. Researchers hypothesize that Aβ interacts with the cell surface preceding neuronal dysfunction and cell death; however, there is no consensus about the functional role of Aβ at the cell surface. Utilizing a mathematical model of a neuron, we compared simulation results under voltage-clamp, current-clamp and high [K+] membrane depolarized conditions of two hypothesized mechanisms of Aβ–neuron interactions: the Aβ blocking of fast-inactivating K+ (IA) channels and the Aβ-induced increase in membrane conductance. Our model predicts that both mechanisms may lead to changes in ion conductances, cell excitability and Ca2+ influx under voltage- and current-clamp conditions. Interestingly, membrane depolarization simulations predict very different correlations in Ca2+ influx between the two mechanisms and may provide data that distinguishes the mechanisms. Our results suggest that our computational modeling methodology may enhance experimental design such that mechanisms of Aβ-induced action on a neuron can be discriminated.

A review on cholinesterase inhibitors for Alzheimer’s disease

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is characterized by the deficits in the cholinergic system and deposition of beta amyloid (Aβ) in the form of neurofibrillary tangles and amyloid plaques. Since the cholinergic system plays an important role in the regulation of learning and memory processes, it has been targetted for the design of anti-Alzheimer's drugs. Cholinesterase inhibitors enhance cholinergic transmission directly by inhibiting the enzyme acetylcholinesterase (AChE) which hydrolyses acetylcholine. Furthermore, it has been also demonstrated that both acetylcholinesterase and butrylcholinesterase (BuChE) play an important role in Aβ-aggregation during the early stages of senile plaque formation. Therefore, AChE and BuChE inhibition have been documented as critical targets for the effective management of AD by an increase in the availability of acetylcholine in the brain regions and decrease in the Aβ deposition. This review discusses the different classes of cholinesterase inhibitors including tacrine, donepezil, rivastigmine, galantamine, xanthostigmine, para-aminobenzoic acid, coumarin, flavonoid, and pyrrolo-isoxazole analogues developed for the treatment of AD.

S100b protects IMR-32 cells against Ab(1-42) induced neurotoxicity via modulation of apoptotic genes expression

Amyloid beta (1-42) peptide is considered responsible for the formation of senile plaques that accumulate in the brain of patients with Alzheimer’s disease (AD). In the past years considerable attention has been focused on identifying new protective substances that prevent or almost retard the appearance of amyloid beta (1-42)-related neurotoxic effects. In this study, human neuroblastoma cells (IMR-32) was used as system model to evaluate the protective role of S100b, a neurotrophic factor and neuronal survival protein, that is highly expressed by reactive astrocytes in close vicinity of beta-amyloid deposits, against amyloid beta (1-42)-dependent toxicity. Our results show that at nanomolar concentrations, S100b protects cells against Aβmediated cytotoxicity, as assessed by MTS vitality test. The protective mechanism seems to be related to the effect on bcl-2 (an anti-apoptotic gene) expression, which is highly down-regulated by amyloid beta (1-42) treatment, while resulted more expressed in the presence of S100b. On the contrary, Bax, a proapoptotic gene, resulted down-regulated by the treatment with S100 compared with the results obtained in the presence of amyloid beta (1-42) peptide. However, at micromolar doses, S100b is toxic for IMR-32 cells and its toxicity adds to that of the Aβpeptide, suggesting that additional molecular mechanisms may be involved in theneurotoxic process.

Biomarkers for Alzheimer’s Disease: Imagination or Reality-View and Review!

The Alzheimer’s disease (AD) is the most widespread chronic, insidious neurodegenerative disease causing dementia in elderly and leading to a massive burden on AD individuals, their families, and on social and health care systems. Its diagnosis is subjective, definite AD can only be diagnosed after pathological brain specimens are examined by either biopsy or autopsy, and it covers 50%-70% of all dementia cases. It is estimated that, by 2050, the number of people aged 80 years or older will approach 370 million worldwide and that 50 percent of those aged 85 years or older will be afflicted with AD. Causes of the disease are multifactorial; where genetics and environmental risk factors work in harmony to cause the disease. Neuropathological features of AD depend on finding of extracellular deposits of β-amyloid peptides (Aβ) that lead to senile plaque formation and intracellular neurofibrillary tangles of hyperphosphory lated tau. However, increasing evidence has suggested that inflammation may play a critical role in AD pathogenesis as well. In the era of genome and sophisticated technology, AD early diagnosis still indecisive and valid biomarkers for AD to be used in routine clinical practice have met with dissatisfaction. Indeed, the relatively unchanged levels of plasma β-amyloid in AD, and a lack of analytical sensitivity for assays for the axonal damage marker have increased the effort to find an alternative ultra-sensitive assay for pathological markers in peripheral blood. We believe that early presymptomalogical practical inexpensive strategies, for characterizing a potential surrogate marker in blood and CSF for AD is warranted, are of interest because they: 1) confirm diagnosis; 2) enable epidemiological screening; 3) identify distinct groups of patients (predictive testing); 4) monitor progression and response to treatment and aid in design/implementation of optimal therapeutic regimens; 5) further the study of the brain-behaviour relationship underlying neurodegeneration.

Alzheimer's disease (AD) as a disorder of the plasma membrane

GENERAL COMMENTARY article Front. Physiol., 15 February 2013Sec. Membrane Physiology and Membrane Biophysics https://doi.org/10.3389/fphys.2013.00024

Extracellular matrix modulator lysyl oxidase colocalizes with amyloid-beta pathology in Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis—Dutch type

Accumulation of amyloid-beta (Aβ) in brain vessel walls and parenchyma, known as cerebral amyloid angiopathy (CAA) and senile plaques (SPs), respectively, plays a key role in Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D) pathogenesis. Although the mechanisms underlying CAA and SP formation remain largely unknown, evidence is mounting that local alterations of the extracellular matrix (ECM) in the brain vessel wall and/or parenchyma play an important role. Lysyl oxidase (LOX, E.C. 1.4.3.13) is an inducible amine oxidase that modulates the ECM by catalyzing the formation of molecular covalent cross-links in ECM proteins. The aim of this study is to investigate the association of LOX with CAA and with classic and diffuse SPs in both AD and HCHWA-D cases. We observed an association of LOX with Aβ in CAA and with Aβ in both classic and diffuse SPs in AD and HCHWA-D cases. In addition, LOX staining was observed in reactive astrocytes associated with these lesions. We conclude that the ECM modulating enzyme LOX is associated with the Aβ-related pathological hallmarks of both AD and HCHWA-D, and that our findings provide additional insights into the mechanisms underlying the formation of these lesions.

How does an animal work?

Summary A newly established interdisciplinary research institute in Lyon, France, aims to bridge the cultural divides between evolution, development, and physiology, in order to study how animal functions come into being, starting from the genomes, and not limited to traditional model systems. Michael Gross reports.

Hyperphosphorylation of Tau Induced by Naturally Secreted Amyloid-β at Nanomolar Concentrations Is Modulated by Insulin-dependent Akt-GSK3β Signaling Pathway

Alzheimer disease (AD) is neuropathologically characterized by the formation of senile plaques from amyloid-β (Aβ) and neurofibrillary tangles composed of phosphorylated Tau. Although there is growing evidence for the pathogenic role of soluble Aβ species in AD, the major question of how Aβ induces hyperphosphorylation of Tau remains unanswered. To address this question, we here developed a novel cell coculture system to assess the effect of extracellular Aβ at physiologically relevant levels naturally secreted from donor cells on the phosphorylation of Tau in recipient cells. Using this assay, we demonstrated that physiologically relevant levels of secreted Aβ are sufficient to cause hyperphosphorylation of Tau in recipient N2a cells expressing human Tau and in primary culture neurons. This hyperphosphorylation of Tau is inhibited by blocking Aβ production in donor cells. The expression of familial AD-linked PSEN1 mutants and APP ΔE693 mutant that induce the production of oligomeric Aβ in donor cells results in a similar hyperphosphorylation of Tau in recipient cells. The mechanism underlying the Aβ-induced Tau hyperphosphorylation is mediated by the impaired insulin signal transduction because we demonstrated that the phosphorylation of Akt and GSK3β upon insulin stimulation is less activated under this condition. Treating cells with the insulin-sensitizing drug rosiglitazone, a peroxisome proliferator-activated receptor γ agonist, attenuates the Aβ-dependent hyperphosphorylation of Tau. These findings suggest that the disturbed insulin signaling cascade may be implicated in the pathways through which soluble Aβ induces Tau phosphorylation and further support the notion that correcting insulin signal dysregulation in AD may offer a potential therapeutic approach.

Molecular docking and receptor-specific 3D-QSAR studies of acetylcholinesterase inhibitors

The reversible inhibition of acetylcholinesterase (AChE) has become a promising target for the treatment of Alzheimer's disease (AD) which is mainly associated with low in vivo levels of acetylcholine (ACh). The availability of AChE crystal structures with and without a ligand triggered the effort to find a structure-based design of acetylcholinesterase inhibitors (AChEIs) for AD. The major problem observed with the structure-based design was the feeble robustness of the scoring functions toward the correlation of docking scores with inhibitory potencies of known ligands. This prompted us to develop new prediction models using the stepwise regression analysis based on consensus of different docking and their scoring methods (GOLD, LigandFit, and GLIDE). In the present investigation, a dataset of 91 molecules belonging to 9 different structural classes of heterocyclic compounds with an activity range of 0.008 to 281,000 nM was considered for docking studies and development of AChE-specific 3D-QSAR models. The model (M1) developed using consensus of docking scores of scoring functions viz. Glide score, Gold score, Chem score, ASP score, PMF score, and DOCK score was found to be the best (R(2) = 0.938, Q(2) = 0.925, R(pred)(2) = 0.919, R(2)m((overall)) = 0.936) compared to other consensus models. Docking studies revealed that the molecules with proper alignment in the active site gorge and the ability to interact with all the crucial amino acid residues, in particular by forming π-π stacking interactions with Trp84 at the catalytic anionic site (CAS) and Trp279 at peripheral anionic site (PAS), showed augmented potencies with consequent improvement in patient cognition and reduced the formation of senile plaques associated with AD. Further, the descriptors that signify the association of the ligands with the receptor as well as ADME properties of the ligands were also analyzed by means of the set of ligands that have been pre-positioned with respect to a receptor after docking analysis and considered as independent variables to generate a linear model (M3 and M4) using a stepwise multiple linear regression method to get additional insight into the physicochemical requirements for effective binding of ligands with AChE as well as for prediction of AChE inhibition. The developed AChE-specific prediction models (M1-M4) satisfactorily reflect the structure-activity relationship of the existing AChEIs and have all the potential to facilitate the process of design and development of new potent AChEIs.

Structural origin of polymorphism of Alzheimer's amyloid β-fibrils

Formation of senile plaques containing amyloid fibrils of Aβ (amyloid β-peptide) is a pathological hallmark of Alzheimer's disease. Unlike globular proteins, which fold into unique structures, the fibrils of Aβ and other amyloid proteins often contain multiple polymorphs. Polymorphism of amyloid fibrils leads to different toxicity in amyloid diseases and may be the basis for prion strains, but the structural origin for fibril polymorphism is still elusive. In the present study we investigate the structural origin of two major fibril polymorphs of Aβ40: an untwisted polymorph formed under agitated conditions and a twisted polymorph formed under quiescent conditions. Using electron paramagnetic resonance spectroscopy, we studied the inter-strand side-chain interactions at 14 spin-labelled positions in the Aβ40 sequence. The results of the present study show that the agitated fibrils have stronger inter-strand spin-spin interactions at most of the residue positions investigated. The two hydrophobic regions at residues 17-20 and 31-36 have the strongest interactions in agitated fibrils. Distance estimates on the basis of the spin exchange frequencies suggest that inter-strand distances at residues 17, 20, 32, 34 and 36 in agitated fibrils are approximately 0.2 Å (1 Å=0.1 nm) closer than in quiescent fibrils. We propose that the strength of inter-strand side-chain interactions determines the degree of β-sheet twist, which then leads to the different association patterns between different cross β-units and thus distinct fibril morphologies. Therefore the inter-strand side-chain interaction may be a structural origin for fibril polymorphism in Aβ and other amyloid proteins.

Formation of spherulitic amyloid β aggregate by anionic liposomes

Alzheimer’s disease is the most common form of senile dementia. This neurodegenerative disorder is characterized by an amyloid deposition in senile plaques, composed primarily of fibrils of an aggregated peptide, amyloid β (Aβ). The modeling of a senile plaque formation on a model neuronal membrane under the physiological condition is an attractive issue. In this study, we used anionic liposomes to model the senile plaque formation by Aβ. The growth behavior of amyloid Aβ fibrils was directly observed, revealing that the induction of the spherulitic Aβ aggregates could result from the growth of seeds in the presence of anionic liposomes. The seeds of Aβ fibrils strongly interacted with negatively charged liposome and the subsequent association of the seeds were induced to form the seed cluster with many growth ends, which is advantageous for the formation of spherulitic Aβ aggregates. Therefore, anionic liposomes mediated not only fibril growth but also the aggregation process. These results imply that anionic liposome membranes would affect the aggregate form of Aβ fibrils. The modeling of senile plaque reported here is considered to have great potential for study on the amyloidosis.

Atorvastatin and pitavastatin reduce senile plaques and inflammatory responses in a mouse model of Alzheimer’s disease

Objectives: To examine and compare the pleiotropic anti-inflammatory effects and the long-term effects of atorvastatin and pitavasatin in mouse model of Alzheimer’s disease (AD).Methods: We examined the effects of two strong statins on senile plaque (SP) size and inflammatory responses in the brain of an amyloid precursor protein (APP) transgenic (Tg) mouse. We gave the Tg mice either atorvastatin or pitavastatin from 5–20 months of age, and performed immunohistological analysis [SP area, monocyte chemotactic protein 1 (MCP-1)-positive neurons, ionized calcium-binding adaptor molecule 1 (Iba-1)-1-positive microglia, and tumor necrosis factor &alpha ( (TNF-α)-positive neurons] every 5 months.Results: In the APP-Tg mice treated with both statins, the number of MCP-1-positive neurons was reduced at 10 months, that of Iba-1-positive microglia was reduced at 15 months, and that of TNF-α-positive neurons and the mean total SP area decreased at 15–20 months, compared with APP-Tg mice with vehicle treatment.Discussion: The protective effect of these statins took 5 months to reach significance in these mice, and the order of sensitivity to statin treatment was MCP-1>Iba-1>TNF-α>SPs. Proinflammatory responses including MCP-1, Iba-1, and TNF-α preceded and possibly contributed to SP formation. Pitavastatin has the same significant pleiotrophic effect to prevent and ameliorate inflammation and also has a long-term effect compared with atorvastatin, and both of them have high potential for a preventative approach in patients at risk of AD.

Selectively Silencing GSK-3 Isoforms Reduces Plaques and Tangles in Mouse Models of Alzheimer's Disease

Glycogen synthase kinase-3 (GSK-3) is linked to the pathogenesis of Alzheimer's disease (AD), senile plaques (SPs), and neurofibrillary tangles (NFTs), but the specific contributions of each of the GSK-3 α and β isoforms to mechanisms of AD have not been clarified. In this study, we sought to elucidate the role of each GSK-3α and GSK-3β using novel viral and genetic approaches. First, we developed recombinant adeno-associated virus 2/1 short hairpin RNA constructs which specifically reduced expression and activity of GSK-3α or GSK-3β. These constructs were injected intraventricularly in newborn AD transgenic (tg) mouse models of SPs (PDAPP⁺/⁻), both SPs and NFTs (PDAPP⁺/⁻;PS19⁺/⁻), or wild-type controls. We found that knockdown (KD) of GSK-3α, but not GSK-3β, reduced SP formation in PDAPP⁺/⁻ and PS19⁺/⁻;PDAPP⁺/⁻ tg mice. Moreover, both GSK-3α and GSK-3β KD reduced tau phosphorylation and tau misfolding in PS19⁺/⁻;PDAPP⁺/⁻ mice. Next, we generated triple tg mice using the CaMKIIα-Cre (α-calcium/calmodulin-dependent protein kinase II-Cre) system to KD GSK-3α in PDAPP⁺/⁻ mice for further study of the effects of GSK-3α reduction on SP formation. GSK-3α KD showed a significant effect on reducing SPs and ameliorating memory deficits in PDAPP⁺/⁻ mice. Together, the data from both approaches suggest that GSK-3α contributes to both SP and NFT pathogenesis while GSK-3β only modulates NFT formation, suggesting common but also different targets for both isoforms. These findings highlight the potential importance of GSK-3α as a possible therapeutic target for ameliorating behavioral impairments linked to AD SPs and NFTs.

Valproic acid attenuates neuronal apoptosis in APP/PS1 transgenic Alzheimer′s disease mice model

One of the hallmarks of Alzheimer's disease (AD) is the accumulation of senile plaques(SP) composed of extracellular aggregates of amyloid ¦Â peptides (A¦Â). It is proved that A¦Â triggers apoptotic cell death via the activation of caspase‐dependent and ‐independent cell death effectors, respectively. Valproic acid (VPA) is a widely used mood stabilizer and antiepileptic drug. Our previous study showed that VPA treatment significantly reduced SP formation and improved memory deficits in AD model mice. The present study intended to explore the protective effect of VPA on neuronal apoptosis in transgenic AD model mice and the possible mechanisms involved. Immunohistochemical staining showed that VPA reduced the number of swollen neurons and promoted neurite outgrowth in AD mice. MTT assay and Tunel staining showed that VPA increased cell viability and reduced the number of apoptotic cells. Western blot revealed that VPA downregulated the expression of Caspase‐ 3, Caspase‐9 and Caspase‐12, reduced cytochrome C level. The expression of Bcl‐2 was increased by VPA treatment. Flow cytometry revealed that VPA decreased intracellular level of Ca2+ and elevated mitochondrial membrane potential. Our results indicate that VPA protected AD mice model via inhibition of both mitochondrial and endoplasmic reticulum pathway of apoptosis.This work was supported by National Natural Science Foundation of China (30970986).

Secondary nucleation of Aβ fibrils on liposome membrane

AbstractThe amyloid fibrils of amyloid β protein (Aβ) from Alzheimer's disease are likely to show the cytotoxicity, depending on their morphology. The relationship between the nucleation kinetics of the Aβ fibrils and their morphology has been investigated. From the perspective of a crystallization technique assuming primary/secondary nucleation steps and an elongation step, the secondary nucleation rate B [# m−3 s−1], was experimentally and coarsely determined by using total internal reflection fluorescence microscopy combined with thioflavin T. In an aqueous solution, linear and rigid fibrils were formed with a relatively smaller B value ((2.83 ± 0.55) × 105 # m−3 s−1), whereas spherulitic amyloid assemblies were formed in the presence of negatively charged liposome including oxidized lipids, with a larger B value ((7.65 ± 0.47) × 105 # m−3 s−1). Those findings should lead to a better understanding of the mechanism for the formation of fibrils and senile plaques in Alzheimer's disease. © 2012 American Institute of Chemical Engineers AIChE J, 2012

Overexpression of Amyloid-β Protein Precursor Induces Mitochondrial Oxidative Stress and Activates the Intrinsic Apoptotic Cascade

Aberrant processing of amyloid-β protein precursor (AβPP) into amyloid-β (Aβ) fragments underlies the formation of senile plaques in Alzheimer's disease (AD). Moreover, Aβ fragments, particularly Aβ(42), exert direct toxic effects within neurons including the induction of mitochondrial oxidative stress (MOS). Interestingly, individuals with Down syndrome (DS) frequently develop early onset AD as a major co-morbid phenotype. One hypothesis for AD associated with DS involves the overexpression of wild type (WT) AβPP protein, due to its location on chromosome 21. However, the mechanism by which the overexpression of WT AβPP might trigger MOS and induce cell death is presently unclear. Here we show that transient overexpression of DsRed2-tagged AβPP (WT) in CHO cells induces caspase-3 activation and nuclear fragmentation indicative of apoptosis. AβPP localizes to the mitochondrial fraction of transfected CHO cells and induces glutathione-sensitive opening of the mitochondrial permeability transition pore (mPTP) and cytochrome c release. MOS and intrinsic apoptosis induced by AβPP are significantly inhibited by co-expression of Bcl-2 or treatment with either glutathione or a pan-caspase inhibitor. The mPTP inhibitor, cyclosporin A, also significantly attenuates AβPP-induced apoptosis. AβPP-induced apoptosis is unaffected by a β-secretase inhibitor and is independent of detectable Aβ(42); however, a γ-secretase inhibitor significantly protects against AβPP overexpression, suggesting a possible role of the AβPP intracellular domain in cell death. These data indicate that overexpression of WT AβPP is sufficient to induce MOS and intrinsic apoptosis, suggesting a novel pro-oxidant role for AβPP at mitochondria which may be relevant in AD and DS disease pathologies.

Correlation of Aβ deposition in the nasal cavity with the formation of senile plaques in the brain of a transgenic mouse model of Alzheimer's disease

The deposition of β-amyloid peptides (Aβ) is commonly reported in the nasal cavity of Alzheimer's disease (AD) patients, although the pathological significance of this finding is unknown. This study compared Aβ concentrations in the nasal area with those in the brain, blood, and cerebrospinal fluid, respectively. Immunohistochemical analysis identified Aβ deposits in the nasal epithelium of Tg2576 mice. Enzyme-linked immunosorbent assay measurements revealed a correlation between the content of Aβ42 in the nasal area and that in the brain, but not with that in the blood. These results suggest that the highly accessible nasal cavity could be a useful site for diagnostic analysis of AD based on Aβ content.

β‐amyloid peptide is internalized into chick retinal neurons and alters the distribution of myosin Vb

The most common neurodegenerative disorder afflicting the aging human population is Alzheimer's disease (AD). A major hallmark of AD is dementia from a loss of neuronal function, attributed to the presence and accumulation of β-amyloid (Aβ) peptide into senile plaques. Preceding senile plaque formation, abnormalities in axons can be observed as changes in morphologies and intracellular trafficking. Recently, it has been recognized that Aβ also accumulates within neurons and this intraneuronal Aβ accumulation has been reported to be critical in the disruption of synapses and cognitive function. Here, we report on the internalization of a fluorescently labeled Aβ peptide into cultured chick retinal neurons. The pattern of Aβ distribution during the time course of incubation is reminiscent of the endocytic pathway. Furthermore, the distribution of the internalized Aβ peptide converges with that of myosin Vb and both relocalize from the axon to cell body. These observations are consistent with the hypothesis that AD proceeds as a result of an imbalance between Aβ production and Aβ clearance, suggesting a role for myosin Vb in this process.

The Role of the Anti-Amyloidogenic Secretase ADAM10 in Shedding the APP-like Proteins

ADAM10 (A disintegrin and metalloproteinase 10) has been demonstrated as an enzyme with protective properties in Alzheimer's disease: in mouse models it not only lowered generation of toxic A-beta peptides and formation of senile plaques but also alleviated learning deficits and enhanced synaptic density. This is due to cleavage of the amyloid precursor protein (APP) within its A-beta stretch and to the release of the extracellular domain of APP with neuroprotective function. Aside from cleaving APP, ADAM10 has been linked to over 40 putative substrates at least in cell culture. These substrates are connected with important cellular functions such as cell migration, stress response and transport. For this contribution we focussed on ADAM10 acting on the APP-like proteins since for some of their representatives - in particular APLP2 and APP-L - a shedding by ADAM10 has been demonstrated in vivo. In addition, the importance of these proteins, especially of APLP2, has been repeatedly shown by intense analysis of double and triple transgenic mice which lack APP in combination with one or both APLPs: several phenotypes such as defects in migration of neuroblasts, in formation of synapses and synaptic transmission have been reported. However, the specific contribution of either the uncleaved full-length proteins or their extracellular domains secreted upon ADAM10 activity has not been elucidated. In this review, we report on recent findings concerning shedding of APP-like proteins and resulting functional consequences.

Molecular Approaches to the Treatment, Prophylaxis, and Diagnosis of Alzheimer’s Disease: Endoplasmic Reticulum Stress and Immunological Stress in Pathogenesis of Alzheimer’s Disease

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder, accompanied by neuronal loss and the formation of senile plaques in the brain. Glial cells, such as microglia, have been shown to be activated and induce chronic inflammatory responses in AD brain. The endoplasmic reticulum (ER) functions to facilitate protein folding. However, ER stress occurs when cells are exposed to stress. Mounting evidence suggests that ER stress is involved in the pathology of AD. Meanwhile, recent findings suggested crosstalk between ER stress and immune function. However, the mechanisms linking the progression of AD with ER and immunological stress are still not clear. In the present paper, we review and discuss recent results regarding the mechanism of AD pathogenesis, focusing on ER stress and immunological stress.