The Adaptive Immune System Restrains Alzheimer’s Disease (AD) Pathogenesis by Modulating Microglial Function
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE77574 | GEO | 2016/03/03
SECONDARY ACCESSION(S): PRJNA310838
REPOSITORIES: GEO
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Project description:Emerging findings suggest that compromised cellular bioenergetics and DNA repair contribute to the pathogenesis of Alzheimer's disease (AD), but their role in disease-defining pathology is unclear. We developed a DNA repair-deficient 3xTgAD/Polb+/- mouse that exacerbates major features of human AD including pTau pathologies, synaptic dysfunction, neuronal death and cognitive impairment. Here we report that 3xTgAD/Polb+/- mice have reduced cerebral NAD+/NADH ratio indicating impaired cerebral energy metabolism, which is normalized by nicotinamide riboside (NR) treatment. NR lessened pTau pathology in both 3xTgAD and 3xTgAD/Polb+/- mice, but had no impact on Abeta accumulation. NR-treated 3xTgAD/Polb+/- mice exhibited reduced DNA damage, neuroinflammation, apoptosis of hippocampal neurons, and increased activity of SIRT3 in the brain. NR improves cognitive function in multiple behavioral tests, and restored hippocampal synaptic plasticity in 3xTgAD mice and 3xTgAD/Polb+/- mice. In general, the deficits and the benefits of NR were greater in 3xTgAD/Polb+/- mice than in 3xTgAD mice. Our findings suggest a pivotal role for cellular NAD+ depletion upstream of neuroinflammation, pTau, DNA damage, synaptic dysfunction and neuronal degeneration in AD. Interventions that bolster neuronal NAD+ levels therefore have potential in AD.
2018-02-26 | GSE109055 | GEO
Project description:We set up a 3D model based on iPSCs derived from patients with familial forms of Alzheimer’s disease (AD) and healthy non-demented control. We created cerebral organoids (COs), verified their ability to mimic AD in vitro, and used it to explore early events and the progression of AD pathogenesis. Our data reveal that despite similar expression of cell-type-specific genes during CO maturation in vitro, AD-iPSCs derived COs show limited tissue patterning and altered cellular development. These findings complement unique single-cell sequencing data of AD-iPSCs derived COs confirming this observation and uncovering that a sub-set of neurons in AD-iPSCs likely differentiates prematurely while at the same time retaining the expression of progenitor marker PAX6.
2022-07-01 | E-MTAB-11438 | biostudies-arrayexpress
Project description:Alzheimer's disease (AD) is associated with the formation of extracellular amyloid-β (Aβ) plaque, perturbing the mechanical properties of brain tissue. Microglia sense and integrate biochemical and mechanical cues in their local microenvironment, intimately linked with AD progress. However, little is known about how microglial mechanosensing pathways are implicated in AD pathogenesis. Gene Ontology (GO) analysis of the significantly down-regulated genes in Piezo1 conditional knockout microglia revealed a significant functional reduction in synapse organization, cell-substrate adhesion, and cytoskeleton system-based events (morphogenesis, migration, and endocytosis) in 5×FAD mice.
2022-03-26 | GSE199217 | GEO
Project description:Cellular senescence has been associated with neurodegenerative disease and clearance of senescent cells using genetic or pharmaceutical strategies (senolytics) has demonstrated beneficial effects in mouse models investigating individual disease etiologies of Alzheimer’s disease (AD). However, it has remained unclear if senescent cell clearance in a mouse model exhibiting both plaque and tau pathologies modifies the disease state (3xTg). Here, we show that treatment with senolytics (ABT263 (navitoclax) or a combination of dasatinib and quercetin (D+Q)) or transgenic removal of p16-expressing cells (via INK-ATTAC) reduced microgliosis and ameliorated both amyloid and tau pathology in 3xTg mice. Using RNA sequencing, we found evidence that synaptic dysfunction and neuroinflammation was attenuated with senescent cell removal. Unfortunately, these beneficial effects were not seen with short-term senolytic treatment in mice with more advanced disease. Overall, our results further corroborate the beneficial effects senescent cell clearance could have on AD and highlight the importance of early intervention for treatment of this debilitating disease.
2024-03-20 | GSE231332 | GEO
Project description:Oxidative stress is a major risk factor for Alzheimer’s disease (AD), which is characterized by brain atrophy, amyloid plaques, neurofibrillary tangles, and loss of neurons. 8-Oxoguanine, a major oxidatively generated nucleobase highly accumulated in the AD brain, is known to cause neurodegeneration. In mammalian cells, several enzymes play essential roles in minimizing the 8-oxoguanine accumulation in DNA. MUTYH with adenine DNA glycosylase activity excises adenine inserted opposite 8-oxoguanine in DNA. MUTYH is reported to actively contribute to the neurodegenerative process in Parkinson and Huntington diseases and some mouse models of neurodegenerative diseases by accelerating neuronal dysfunction and microgliosis under oxidative conditions; however, whether or not MUTYH is involved in AD pathogenesis remains unclear. In the present study, we examined the contribution of MUTYH to the AD pathogenesis. Using postmortem human brains, we showed that various types of MUTYH transcripts and proteins are expressed in most hippocampal neurons and glia in both non-AD and AD brains. We further introduced MUTYH deficiency into AppNL-G-F/NL-G-F knock-in AD model mice, which produce humanized toxic amyloid-β without the overexpression of APP protein, and investigated the effects of MUTYH deficiency on the behavior, pathology, gene expression, and neurogenesis. MUTYH deficiency improved memory impairment in AppNL-G-F/NL-G-F mice, accompanied by reduced microgliosis. Gene expression profiling strongly suggested that MUTYH is involved in the microglial response pathways under AD pathology and contributes to the phagocytic activity of disease-associated microglia. We also found that MUTYH deficiency ameliorates impaired neurogenesis in the hippocampus, thus improving memory impairment. In conclusion, we propose that MUTYH, which is expressed in the hippocampus of AD patients as well as non-AD subjects, actively contributes to memory impairment by inducing microgliosis with poor neurogenesis in the preclinical AD phase and that MUTYH is a novel therapeutic target for AD, as its deficiency is highly beneficial for ameliorating AD pathogenesis.
2021-12-23 | GSE157766 | GEO
Project description:Kyrtsos2011 - A systems biology model for
Alzheimer's disease (Cholesterol in AD)
Encoded non-curated model. Issues:
- Confusing HmgCoA differential equation
- Confusing d2 and t1 parameters
- Lack of initial values for several key species
This model is described in the article:
Of Mice and Math: A Systems
Biology Model for Alzheimer's disease
Kyrtsos, Christina Rose
UMD Theses and Dissertations
Abstract:
Alzheimer's disease (AD) is the most prevalent
neurodegenerative disorder in the US, affecting over 1 in 8
people over the age of 65. There are several well-known
pathological changes in the brains of AD patients, namely: the
presence of diffuse beta amyloid plaques derived from the
amyloid precursor protein (APP), hyper-phosphorylated tau
protein, neuroinflammation and mitochondrial dysfunction.
Recent studies have shown that cholesterol levels in both the
plasma and the brain may play a role in disease pathogenesis,
however, this exact role is not well understood. Additional
proteins of interest have also been identified (ApoE, LRP-1,
IL-1) as possible contributors to AD pathogenesis. To help
understand these roles better, a systems biology mathematical
model was developed. Basic principles from graph theory and
control analysis were used to study the effect of altered
cholesterol, ApoE, LRP and APP on the system as a whole.
Negative feedback regulation and the rate of cholesterol
transfer between astrocytes and neurons were identified as key
modulators in the level of beta amyloid. Experiments were run
concurrently to test whether decreasing plasma and brain
cholesterol levels with simvastatin altered the expression
levels of beta amyloid, ApoE, and LRP-1, to ascertain the edge
directions in the network model and to better understand
whether statin treatment served as a viable treatment option
for AD patients. The work completed herein represents the first
attempt to create a systems-level mathematical model to study
AD that looks at intercellular interactions, as well as
interactions between metabolic and inflammatory pathways.
This model is hosted on
BioModels Database
and identified by:
MODEL1504240000.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2016-05-09 | MODEL1504240000 | BioModels
Project description:Deposition of amyloid beta (Aβ) and hyperphosphorylated tau along with glial cell-mediated neuroinflammation are prominent pathogenic hallmarks of Alzheimer’s disease (AD). In recent years, impairment of autophagy has been found to be another important feature contributing to AD progression. Therefore, the potential of the autophagy activator spermidine, a small body-endogenous polyamine often used as dietary supplement, was assessed on Aβ pathology and glial cell-mediated neuroinflammation. Oral treatment of the amyloid prone AD-like APPPS1 mice with spermidine reduced neurotoxic soluble Aβ and decreased AD-associated neuroinflammation during disease progression. Mechanistically, single nuclei sequencing revealed AD-associated microglia to be the main target of spermidine. This microglia population was characterized by increased AXL levels and expression of genes implicated in cell migration and phagocytosis. Our data highlight that the autophagy activator spermidine holds the potential to enhance Aβ degradation and to counteract glia-mediated neuroinflammation in AD pathology.
2022-07-04 | GSE206202 | GEO
Project description:Microglial activation during neuroinflammation is crucial for coordinating the immune response against neuronal tissue and the initial response of microglia determines the severity of neuroinflammatory diseases. CD83 has been associated with early activation of microglia in various disease settings albeit its functional relevance for microglial biology was still elusive. Thus, we conducted a thorough assessment of CD83 regulation in microglia as well as its impact on microglial mediated neuroinflammation. Here, we describe for the first time that CD83 expression in microglia is not only associated with cellular activation but also with pro-resolving functions. Conditional deletion of CD83 causes malfunctioning responses to myelin debris, which results in an over-activated state during autoimmune neuroinflammation. Subsequently, CD83-deficient microglia recruit more pathogenic immune cells to the central nervous system and deteriorate resolving mechanism, which exacerbates the disease. Thus, CD83 in microglia orchestrates cellular activation and consequently, also resolution of neuroinflammation.
2023-06-28 | GSE230753 | GEO
Project description:Deposition of amyloid beta (Aβ) and hyperphosphorylated tau along with glial cell-mediated neuroinflammation are prominent pathogenic hallmarks of Alzheimer’s disease (AD). In recent years, impairment of autophagy has been found to be another important feature contributing to AD progression. Therefore, the potential of the autophagy activator spermidine, a small body-endogenous polyamine often used as dietary supplement, was assessed on Aβ pathology and glial cell-mediated neuroinflammation. Oral treatment of the amyloid prone AD-like APPPS1 mice with spermidine reduced neurotoxic soluble Aβ and decreased AD-associated neuroinflammation. A subsequent proteome analysis of isolated microglia confirmed the anti-inflammatory and revealed cytoskeletal effects of spermidine in APPPS1 mice. Our data highlight that the autophagy activator spermidine holds the potential to enhance Aβ degradation and to counteract microglia-mediated neuroinflammation in AD pathology.
2022-07-04 | PXD034638 | Pride
Project description:The assay for transposase-accessible chromatin by sequencing (ATAC-seq) was used to investigate the AD-associated chromatin reshaping in the APPswe/PS1dE9 (APP/PS1) mouse model. ATAC-seq data in the hippocampus of 8-month-old APP/PS1 mice were generated, and the relationship between chromatin accessibility and gene expression was analyzed in combination with RNA-sequencing.We identified 1690 increased AD-associated chromatin accessible regions in the hippocampal tissues of APP/PS1 mice and 1003 decreased chromatin accessible regions were considered to be related with declined AD-associated biological processes.In the APP/PS1 hippocampus, 1090 genes were found to be up-regulated and 1081 down-regulated. Interestingly, enhanced ATAC-seq signal was found in approximately 740 genes, with 43 exhibiting up-regulated mRNA levels.Our study reveals that alterations in chromatin accessibility may be an initial mechanism in AD pathogenesis.
2020-07-09 | GSE145907 | GEO