Alzheimer's Pathway Research Articles

Basal forebrain metabolism in Alzheimer's disease continuum: relationship with education

We analyzed education, as a proxy of cognitive reserve, and the cholinergic pathway in Alzheimer's disease (AD), to test the hypothesis that education might modulate the relationship between clinical symptoms and metabolic and structural changes in AD. We included 84 subjects and compared between diagnostic groups and different educational levels the glucose metabolism of basal forebrain (BFM) and volume of the basal forebrain, the major cholinergic structure, and hippocampus (HM) (and hippocampal volume), a relevant projection site for the basal forebrain. Correlations with the global cognitive status and education in the whole sample were also performed. Patients with AD dementia showed reduced basal forebrain volume, hippocampal volume, and HM compared with controls. In the whole group, the global cognitive status was positively correlated with BFM and HM. Among high-educated subjects, mild cognitive impairment showed higher BFM and HM in comparison to other diagnostic groups. Our results suggest that in mild cognitive impairment subjects with a higher educational level, cholinergic activity is upregulated and this appears to have a compensatory effect, which may be lost in later symptomatic stages.

Systemic Immune Dyshomeostasis Model and Pathways in Alzheimer's Disease.

Alzheimer’s disease (AD) still remains an enigma for researchers and clinicians. The onset of AD is insidious, gradually progressive and multifactorial. The recent accumulated scientific evidences suggests that the pathological changes resemble the autoimmune-driven self-sustaining inflammatory process as a result of prolonged oxidative stress and immune dyshomeostasis. Apart from aging, during life span various other factors—mainly environmental, lifestyle, chronic stress, polymicrobial infections and neuroendocrine functions—affect the immune system. Here, we provide crosstalk among “trigger insults/inflammatory stimulus” i.e., polymicrobial infection, chronic stress, pro-inflammatory diet and cholinergic signaling to put forward a “Systemic Immune Dyshomeostasis” model as to connect the events leading to AD development and progression. Our model implicates altered cholinergic signaling and suggests pathological stages with various modifiable risk factors and triggers at different chronological age and stage of cognitive decline. The search of specific autoantibodies for AD which may serve as the suitable blood/CSF biomarkers should be actively pursued for the early diagnosis of AD. The preventive and therapeutic strategies should be directed towards maintaining the normal functioning of the immune system throughout the life span and specific modulation of the immune responses in the brain depending on the stage of changes in brain.

The complement cascade in Alzheimer's disease: a systematic review and meta-analysis.

Genetic evidence implicates a causal role for the complement pathway in Alzheimer's disease (AD). Since studies have shown inconsistent differences in cerebrospinal fluid (CSF) and peripheral blood complement protein concentrations between AD patients and healthy elderly, this study sought to summarize the clinical data. Original peer-reviewed articles measuring CSF and/or blood concentrations of complement or complement regulator protein concentrations in AD and healthy elderly control (HC) groups were included. Of 2966 records identified, means and standard deviations from 86 studies were summarized as standardized mean differences (SMD) by random effects meta-analyses. In CSF, concentrations of clusterin (NAD/NHC = 625/577, SMD = 0.53, Z8 = 8.81, p < 0.005; I2 < 0.005%) and complement component 3 (C3; NAD/NHC = 299/522, SMD = 0.45, Z3 = 3.21, p < 0.005; I2 = 68.40%) were significantly higher in AD, but differences in C1q, C-reactive protein (CRP), serum amyloid protein (SAP), and factor H concentrations were not significant. In peripheral blood, concentrations of CRP were elevated in AD (NAD/NHC = 3404/3332, SMD = 0.44, Z43 = 3.43, p < 0.005; I2 = 93.81%), but differences between groups in C3, C4, C1-inhibitor, SAP, factor H and clusterin concentrations were not significant,and inconsistent between studies. Of 64 complement pathway proteins or regulators in the quantitative synthesis, trends in C1q, factor B, C4a, and late-stage complement pathway components (e.g. C9) in blood, C4 in CSF, and the membrane attack complex in blood and CSF, might be investigated further. The results collectively support elevated complement pathway activity in AD, which was best characterized by increased CSF clusterin concentrations and less consistently by CSF C3 concentrations. Complement activity related to anADdiagnosis was not reflected consistently by the peripheral blood proteins investigated.

Complement pathway in Alzheimer's pathology and retinal neurodegenerative disorders - the road ahead.

Complement pathway in Alzheimer's pathology and retinal neurodegenerative disorders - the road ahead.

Integrated identification of key genes and pathways in Alzheimer\u2019s disease via comprehensive bioinformatical analyses

BackgroundAlzheimer’s disease (AD) is known to be caused by multiple factors, meanwhile the pathogenic mechanism and development of AD associate closely with genetic factors. Existing understanding of the molecular mechanisms underlying AD remains incomplete.MethodsGene expression data (GSE48350) derived from post-modern brain was extracted from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were derived from hippocampus and entorhinal cortex regions between AD patients and healthy controls and detected via Morpheus. Functional enrichment analyses, including Gene Ontology (GO) and pathway analyses of DEGs, were performed via Cytoscape and followed by the construction of protein-protein interaction (PPI) network. Hub proteins were screened using the criteria: nodes degree≥10 (for hippocampus tissues) and ≥ 8 (for entorhinal cortex tissues). Molecular Complex Detection (MCODE) was used to filtrate the important clusters. University of California Santa Cruz (UCSC) and the database of RNA-binding protein specificities (RBPDB) were employed to identify the RNA-binding proteins of the long non-coding RNA (lncRNA).Results251 & 74 genes were identified as DEGs, which consisted of 56 & 16 up-regulated genes and 195 & 58 down-regulated genes in hippocampus and entorhinal cortex, respectively. Biological analyses demonstrated that the biological processes and pathways related to memory, transmembrane transport, synaptic transmission, neuron survival, drug metabolism, ion homeostasis and signal transduction were enriched in these genes. 11 genes were identified as hub genes in hippocampus and entorhinal cortex, and 3 hub genes were identified as the novel candidates involved in the pathology of AD. Furthermore, 3 lncRNAs were filtrated, whose binding proteins were closely associated with AD.ConclusionsThrough GO enrichment analyses, pathway analyses and PPI analyses, we showed a comprehensive interpretation of the pathogenesis of AD at a systematic biology level, and 3 novel candidate genes and 3 lncRNAs were identified as novel and potential candidates participating in the pathology of AD. The results of this study could supply integrated insights for understanding the pathogenic mechanism underlying AD and potential novel therapeutic targets.

Integration of probabilistic regulatory networks into constraint-based models of metabolism with applications to Alzheimer\u2019s disease

BackgroundMathematical models of biological networks can provide important predictions and insights into complex disease. Constraint-based models of cellular metabolism and probabilistic models of gene regulatory networks are two distinct areas that have progressed rapidly in parallel over the past decade. In principle, gene regulatory networks and metabolic networks underly the same complex phenotypes and diseases. However, systematic integration of these two model systems remains a fundamental challenge.ResultsIn this work, we address this challenge by fusing probabilistic models of gene regulatory networks into constraint-based models of metabolism. The novel approach utilizes probabilistic reasoning in BN models of regulatory networks serves as the “glue” that enables a natural interface between the two systems. Probabilistic reasoning is used to predict and quantify system-wide effects of perturbation to the regulatory network in the form of constraints for flux variability analysis. In this setting, both regulatory and metabolic networks inherently account for uncertainty. Applications leverage constraint-based metabolic models of brain metabolism and gene regulatory networks parameterized by gene expression data from the hippocampus to investigate the role of the HIF-1 pathway in Alzheimer’s disease. Integrated models support HIF-1A as effective target to reduce the effects of hypoxia in Alzheimer’s disease. However, HIF-1A activation is far less effective in shifting metabolism when compared to brain metabolism in healthy controls.ConclusionsThe direct integration of probabilistic regulatory networks into constraint-based models of metabolism provides novel insights into how perturbations in the regulatory network may influence metabolic states. Predictive modeling of enzymatic activity can be facilitated using probabilistic reasoning, thereby extending the predictive capacity of the network. This framework for model integration is generalizable to other systems.

Emodin attenuates Alzheimer's disease by activating the protein kinase C signaling pathway

To investigate the effects of emodin on learning and memory and protein kinase C (PKC) signaling pathway in Alzheimer's disease (AD) model mice. 60 APP/PS1 double transgenic AD mice were selected as model mice at the age of 7-8 months, 36 healthy male C57BL/6 mice served as the control group. Morris water maze method and passive avoidance experiment were used to evaluate the memory ability of mice. The thiazole blue (MTT) method and the lactate dehydrogenase (LDH) cytotoxicity test kit were used to evaluate the effect of emodin on the cell viability of hippocampal neurons in HT22 mice treated with β-amyloid peptide 1-42 (Aβ1-42). The effect of emodin on PKC levels was explored using the modified Takai method and Western blotting. Behavioral test results showed that the escape latency of the mice in the model group was longer than that in the control group (P&lt;0.05), and the escape latency was significantly shortened given a emodin prognosis. The MTT and LDH test results showed that emodin to Aβ- overexpression induced the protective effect of hippocampus cells in HT22 mice. Western blot analysis showed that the phosphorylation level of PKC in mice increased significantly after emodin administration. Emodin can attenuate oxidative stress and inflammatory response in Alzheimer's model mice by activating PKC pathway, thereby improving cognitive function.

Dissecting Alzheimer's Disease Molecular Substrates by Proteomics and Discovery of Novel Post-translational Modifications.

Alzheimer's disease (AD) is a common complex disease and a major public health burden in both developed and developing countries. Postgenomic technologies such as proteomics and intelligent mining of multi-omics Big Data offer new prospects for diagnostics and therapeutics innovation for AD. In this context, it is noteworthy that mass spectrometry (MS) data are often searched against proteomics databases to unravel the identity of protein biomarkers. In contrast, only a fraction of the MS data can be matched to known proteins, while a large portion of such raw data remains underutilized. Furthermore, the spectral data can be mined for multiple high-confidence post-translational modifications (PTMs) without a priori enrichment. Thus, AD research stands to gain by greater attention to the biological mechanisms regulated by PTMs. Protein modifications may serve as diagnostic biomarkers or as novel molecular targets for drug discovery. We report here novel PTMs discovered in relation to the AD from MS/MS-based proteomic datasets. Publicly available label-free proteomics data were searched for select PTMs using SEQUEST-HT. Only high-confidence PTMs were analyzed using bioinformatics analysis. We identified 4961 unique modified peptides corresponding to 1856 proteins from AD datasets. Of these, 52 proteins were known to be involved in Alzheimer's pathway. Importantly, 3164 PTMs reported in this study are novel in the context of AD. Furthermore, protein quantification revealed expression of 13 high-abundant secretary proteins across multiple studies, which can be potentially harnessed in the future to develop biomarkers. In summary, this study identifies novel PTMs which might help develop new insights on the molecular substrates of AD and thus inform future development of novel diagnostics and treatments for this highly prevalent disease.

Intrahippocampal miR-342-3p inhibition reduces β-amyloid plaques and ameliorates learning and memory in Alzheimer's disease.

Accumulation of extracellular amyloid-β (Aβ) in hippocampal subregions is a hallmark of Alzheimer's disease (AD), which promotes neuronal apoptosis, potentiates cognitive decline and play a causative role in AD pathogenesis. However, whether this process is controlled by distinct miRNAs at the posttranscriptional level remain fascinating but poorly understood. Using post mortem hippocampal samples from human AD patients and 3xTg-AD mouse, we demonstrate that miR-342-3p expression was significantly induced during the AD development. With the aid of intrahippocampal injection of miR-342-3p antagomir, we further show that in vivo miR-342-3p inhibition synergistically improved cognitive deficits in 3xTg-AD mice. The hippocampal Aβ-plaque burden in 3xTg-AD mice, as revealed by immunohistochemical analysis with 4G8 antibody, was attenuated also. Mechanistically, the upregulation of neuronal miR-342-3p is linked to an increase in the activation of the stress kinase c-Jun N-terminal kinase with the subsequent death of the neurons in Aβ-challenged HT22 hippocampal neuronal cells. These findings support the model that derangement of hippocampus signal transduction and subsequent neuronal apoptosis in AD arises as a consequence of increased Aβ burden and chronic activation of the JNK MAPK cascade in a miR-342-3p-dependent manner. Overall, we described for the first time the regulatory activity of miR-342-3p on relevant Aβ metabolism pathways in Alzheimer's disease.

Roles of Mammalian Target of Rapamycin Signaling and Autophagy Pathway in Alzheimer's Disease

The mammalian target of rapamycin(mTOR)is a serine/threonine protein kinase that regulates protein synthesis and degradation,cytoskeletal formation,and cell longevity.Autophagy,a catabolic process necessary for the maintenance of intracellular homeostasis,is essential for cell survival,whereas mTOR is the crucial regulator of autophagy.Alzheimer's disease(AD)is the most common cause of progressive dementia in the elderly.It has been shown that disorders of mTOR and autophagy signaling pathways are closely related to AD.In the present review,we describe the regulatory roles of mTOR signaling and autophagy pathway in AD brain and introduce drugs for AD acting via modulation of autophagy and mTOR.

A Meta-Analysis of Alzheimer's Disease Brain Transcriptomic Data.

Background:Microarray technologies have identified imbalances in the expression of specific genes and biological pathways in Alzheimer’s disease (AD) brains. However, there is a lack of reproducibility across individual AD studies, and many related neurodegenerative and mental health disorders exhibit similar perturbations.Objective:Meta-analyze publicly available transcriptomic data from multiple brain-related disorders to identify robust transcriptomic changes specific to AD brains.Methods:Twenty-two AD, eight schizophrenia, five bipolar disorder, four Huntington’s disease, two major depressive disorder, and one Parkinson’s disease dataset totaling 2,667 samples and mapping to four different brain regions (temporal lobe, frontal lobe, parietal lobe, and cerebellum) were analyzed. Differential expression analysis was performed independently in each dataset, followed by meta-analysis using a combining p-value method known as Adaptively Weighted with One-sided Correction.Results:Meta-analysis identified 323, 435, 1,023, and 828 differentially expressed genes specific to the AD temporal lobe, frontal lobe, parietal lobe, and cerebellum brain regions, respectively. Seven of these genes were consistently perturbed across all AD brain regions with SPCS1 gene expression pattern replicating in RNA-Seq data. A further nineteen genes were perturbed specifically in AD brain regions affected by both plaques and tangles, suggesting possible involvement in AD neuropathology. In addition, biological pathways involved in the “metabolism of proteins” and viral components were significantly enriched across AD brains.Conclusion:This study identified transcriptomic changes specific to AD brains, which could make a significant contribution toward the understanding of AD disease mechanisms and may also provide new therapeutic targets.

Glutamine Improves Oxidative Stress through the Wnt3a/β-Catenin Signaling Pathway in Alzheimer's Disease In Vitro and In Vivo.

Background/Aims Alzheimer's disease (AD) is the most common neurodegenerative disease, and all researchers working in this field agree that oxidative stress is intimately associated with Alzheimer disease. In this study, we hypothesized that glutamine (Gln) offers protection against oxidative stress injury in SAMP8 mice as well as the underlying mechanism. Methods The SAMP8 mice received glutamine intragastrically for 8 consecutive weeks to evaluate the protective effect of glutamine on oxidative stress in AD mice involving Wnt3a/β-catenin signaling pathway. In addition, rat pheochromocytoma tumor cell line PC12 was pretreated with 32 μM glutamine for 2 h followed by 24 h incubation with 40 μM Aβ25-35 to obtain in vitro data. Results In vivo the administration of glutamine was found to ameliorate behavioral deficits and neuron damage, increase superoxide dismutase (SOD) and glutathione peroxidase (GSH-XP) activity, reduce the malondialdehyde (MDA) content, and activate the Wnt3a/β-catenin signaling pathway in SAMP8 mice. In vitro glutamine treatment decreased the toxicity of Aβ25-35 on PC12 cells and prevented apoptosis. Additionally, glutamine treatment increased SOD and GSH-XP activity and decreased MDA content and increased Wnt3a and β-catenin protein levels. Interestingly, the DKK-1 (Wnt3a/β-catenin pathway inhibitor) decreased the antioxidant capacity of glutamine in Aβ25-35-treated PC12 cells. Conclusion This study suggests that glutamine could protect against oxidative stress-induced injury in AD mice via the Wnt3a/β-catenin signaling pathway.

Targeting Inflammatory Pathways in Alzheimer's Disease: A Focus on Natural Products and Phytomedicines.

Studies of the brains of Alzheimer's disease (AD) patients have revealed key neuropathological features, such as the deposition of aggregates of insoluble amyloid-β (Aβ) peptides and neurofibrillary tangles (NFTs). These pathological protein deposits, including Aβ peptides (which form senile plaques) and hyperphosphorylated tau (which aggregates into NFTs), have been assumed to be 'the cause of AD'. Aβ has been extensively targeted to develop an effective disease-modifying therapy, but with limited clinical success. Emerging therapies are also now targeting further pathological processes in AD, including neuroinflammation. This review focuses on the inflammatory and oxidative stress-related changes that occur in AD, and discusses some emerging anti-inflammatory natural products and phytomedicines. Many of the promising compounds are cytokine-suppressive anti-inflammatory drugs (CSAIDs), which target the proinflammatory AP1 and nuclear factor-κB signalling pathways and inhibit the expression of many proinflammatory cytokines, such as interleukin (IL)-1, IL-6, tumour necrosis factor-α, or nitric oxide produced by inducible nitric oxide synthase. However, many of these phytomedicines have not been tested in rigorous clinical trials in AD patients. It is not yet clear if the active compounds reach an effective concentration in the brain (due to limited bioavailability) or if they can slow down AD progression in long-term trials. The authors suggest that it is crucial for both the pharmacological and complementary medicine industries to conduct and fund those studies to significantly advance the field.

Choroid plexus tumor necrosis factor receptor 1: A new neuroinflammatory piece of the complex Alzheimer's disease puzzle.

Due to the aging of the population and despite the enormous scientific effort, Alzheimer’s disease remains one of the biggest medical and pharmaceutical challenges in current medicine. Novel insights highlight the importance of neuroinflammation as an undeniable player in the onset and progression of Alzheimer’s disease. Tumor necrosis factor is a master inflammatory cytokine that signals via tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2, but that also regulates several brain functions in health and disease. However, clinical trials investigating drugs that interfere with the tumor necrosis factor pathway in Alzheimer’s disease led to inconclusive results, partially because not only the pro-inflammatory tumor necrosis factor/tumor necrosis factor receptor 1, but also the beneficial tumor necrosis factor/tumor necrosis factor receptor 2 signaling was antagonized in these trials. We recently found that tumor necrosis factor is the main upregulated cytokine in the choroid plexus of Alzheimer’s disease patients, signaling via tumor necrosis factor receptor 1. In agreement with this, choroidal tumor necrosis factor/tumor necrosis factor receptor 1 signaling was also upregulated in different Alzheimer’s disease mouse models. Interestingly, both genetic and nanobody-based pharmacological blockage of tumor necrosis factor receptor 1 signaling was accompanied by favorable effects on Alzheimer’s disease-associated inflammation, choroidal morphology and cognitive functioning. Here, we briefly summarize the detrimental effects that can be mediated by tumor necrosis factor/tumor necrosis factor receptor 1 signaling in (early) Alzheimer’s disease, and the consequences this might have on the disease progression. As the main hypothesis in Alzheimer’s disease clinical trials is still based on the amyloid beta-cascade, the importance of Alzheimer’s disease-associated neuroinflammation urge the development of novel therapeutic strategies that might be effective in the early stages of Alzheimer’s disease and prevent the irreversible neurodegeneration and resulting memory decline.

RETRACTED: Osthole decreases tau protein phosphorylation via PI3K/AKT/GSK-3β signaling pathway in Alzheimer's disease

Alzheimer's disease (AD), a neurodegenerative disease, was characterized by the loss of memory and progressive cognitive deterioration. Up to now, there has no effective drugs to cure or delay the state of illness. Increasing evidence indicates that hyperphosphorylated tau protein plays a pivotal role in the occurrence and development of AD. Therefore, in present study, we aim to investigate whether osthole (OST) could decrease hyperphosphorylated tau protein in AD and the underlying mechanism. The ability of learning and memory was detected by Morris Water Maze. The pathological changes were detected by H&E staining. The percentage of cells apoptosis was detected by TUNEL assay in vivo and Flow Cytometry in intro. The expressions of tau protein and related proteins in PI3K/Akt/GSK-3β signaling pathway were detected by Western Blot. We found that OST could significantly improve learning and memory dysfunction, ameliorate the histology structure of damaged neural cells in hippocampal area. Moreover, we also found that OST could decrease tau protein phosphorylation as well as inhibit cells apoptosis. To explore the underlying mechanism, we used LY294002 to block PI3K/Akt/GSK-3β signaling pathway, the results from Western bolt showed that the expression of related proteins in PI3K signaling pathway were decreased with LY294002 treated. Taken together, the results indicated that OST could decrease phosphorylated tau levels via activation of PI3K/Akt/GSK-3β signaling pathway. Thus, this study demonstrated that OST might be a potential candidate for the treatment of AD.

Greater tau load and reduced cortical thickness in APOE \u03b54-negative Alzheimer\u2019s disease: a cohort study

BackgroundAlzheimer’s disease is characterized by aggregated β-amyloid and tau proteins, but the clinical presentations and patterns of brain atrophy vary substantially. A part of this heterogeneity may be linked to the risk allele APOE ε4. The spread of tau pathology is related to atrophy and cognitive decline, but little data exist on the effects of APOE ε4 on tau. The objective of this preliminary study was therefore to test if tau load and brain structure differ by APOE ε4 in Alzheimer’s disease.MethodsSixty-five β-amyloid-positive patients at the prodromal and dementia stages of Alzheimer’s disease were enrolled, including APOE ε4-positive (n = 46) and APOE ε4-negative (n = 19) patients. 18F-AV-1451 positron emission tomography was used to measure tau and brain magnetic resonance imaging (MRI) was used to measure cortical thickness.ResultsCompared with their APOE ε4-positive counterparts, APOE ε4-negative patients had greater tau load and reduced cortical thickness, with the most pronounced effects for both in the parietal cortex. Relative to the overall cortical tau load, APOE ε4-positive patients had greater tau load in the entorhinal cortex. APOE ε4-positive patients also had slightly greater cortical β-amyloid load. There was an interaction between APOE ε4 and 18F-AV-1451 on cortical thickness, with greater effects of 18F-AV-1451 on cortical thickness in APOE ε4-negative patients. APOE ε4 and 18F-AV-1451 were independent predictors of cognition, but showed distinct associations with different cognitive tests.ConclusionsAPOE genotype may be associated with differences in pathways in Alzheimer’s disease, potentially through differential development and spread of tau, as well as through effects on cognitive outcomes involving non-tau-related mechanisms.

The emerging roles of protein homeostasis-governing pathways in Alzheimer's disease.

Pathways governing protein homeostasis are involved in maintaining the structural, quantitative, and functional stability of intracellular proteins and involve the ubiquitin–proteasome system, autophagy, endoplasmic reticulum, and mTOR pathway. Due to the broad physiological implications of protein homeostasis pathways, dysregulation of proteostasis is often involved in the development of multiple pathological conditions, including Alzheimer's disease (AD). Similar to other neurodegenerative diseases that feature pathogenic accumulation of misfolded proteins, Alzheimer's disease is characterized by two pathological hallmarks, amyloid‐β (Aβ) plaques and tau aggregates. Knockout or transgenic overexpression of various proteostatic components in mice results in AD‐like phenotypes. While both Aβ plaques and tau aggregates could in turn enhance the dysfunction of these proteostatic pathways, eventually leading to apoptotic or necrotic neuronal death and pathogenesis of Alzheimer's disease. Therefore, targeting the components of proteostasis pathways may be a promising therapeutic strategy against Alzheimer's disease.

Histone acetylation maps in aged mice developmentally exposed to lead: epigenetic drift and Alzheimer-related genes.

Early life exposure to lead (Pb) has been shown to increase late life biomarkers involved in Alzheimer's disease (AD) pathology. Here, we tested the hypothesis that latent over expression of AD-related genes may be regulated through histone activation pathways. Chromatin immunoprecipitation sequencing was used to map the histone activation mark (H3K9Ac) to the mouse genome in developmentally Pb exposed mice on postnatal days 20, 270 and 700. Exposure to Pb resulted in a global downregulation of H3K9Ac across the lifespan; except in genes associated with the Alzheimer pathway. Early life exposure to Pb results in an epigenetic drift in H3K9Ac consistent with latent global gene repression. Alzheimer-related genes do not follow this trend.

Altered DNA repair; an early pathogenic pathway in Alzheimer\u2019s disease and obesity

Unrepaired DNA double-strand breaks (DSBs) are lethal. The present study compared the extent of DSBs, neuronal apoptosis, and status of two major DSB repair pathways - homologous combinational repair (HR) and nonhomologous end-joining (NHEJ) - in hippocampus of 5–6 month and 16–18 month-old wild-type and APP/PSEN1 mice fed control diet or high fat diet (60% fat from lard). We performed immunohistochemical staining and quantification for nuclear foci formation of γ-H2AX for DSBs, RAD51, and 53BP1, which represent the functional status of HR and NHEJ, respectively. Increased γ-H2AX and caspase-3 staining indicated greater DSBs and associated neuronal apoptosis in APP/PSEN1 mice at both ages studied. RAD51-positive foci were fewer in APP/PSEN1 indicating that HR processes may be diminished in these mice, although NHEJ (53BP1 staining) appeared unchanged. High fat diet in young wild-type mice led to similar changes to those observed in APP/PSEN1 mice (γ-H2AX and caspase-3 staining, and fewer RAD51-positive foci). Overall, these data suggest that APP/PSEN1- and high fat diet-associated early accumulation of DSBs and neuronal cell death, resulted at least in part, from inhibition of HR, one of the major DSB repair pathways.

Dysregulation of Rab5-mediated endocytic pathways in Alzheimer's disease.

Increasing evidence has pointed to that dysregulation of the endo-lysosomal system is an early cellular phenotype of pathogenesis for Alzheimer's disease (AD). Rab5, a small GTPase, plays a critical role in mediating these processes. Abnormal overactivation of Rab5 has been observed in post-mortem brain samples of Alzheimer's patients as well as brain samples of mouse models of AD. Recent genome-wide association studies of AD have identified RIN3 (Ras and Rab interactor 3) as a novel risk factor for the disease. RIN3 that functions as a guanine nucleotide exchange factor for Rab5 may serve as an important activator for Rab5 in AD pathogenesis. In this review, we present recent research highlights on the possible roles of dysregulation of Rab5-mediated endocytic pathways in contributing to early pathogenesis of AD.