Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The major risk factors for Alzheimer’s disease: Age, Sex and Genes, modulate the microglia response to Aβ plaques (KW)

ABSTRACT: Microglia are involved in Alzheimer’s disease (AD) by adopting activated phenotypes. How ageing in the absence or presence of β-amyloid (Aβ) deposition in different brain areas affects this response and whether sex and AD risk genes are involved, remains however largely unknown. Here we analyzed the gene expression profiles of more than 10,000 individual microglia cells isolated from cortex and hippocampus of male and female AppNL-G-F at 4 different stages of Aβ deposition and in age-matched control mice. We demonstrate that microglia adopt two major activated states during normal aging and after exposure to amyloid plaques. One of the responses (activated response microglia, ARM) is enhanced in particular by amyloid plaques and is strongly enriched with AD risk genes. The ARM response is not homogeneous, as subgroups of microglia overexpressing MHC type II and tissue repair genes (Dkk2, Gpnmb, Spp1) are induced upon prolonged Aβ exposure. Microglia in female mice advance faster in the activation trajectories. Similar activated states were also found in a second AD model and in human brain. We demonstrate that abolishing the expression of Apoe, the major genetic risk factor for AD, impairs the establishment of ARMs, while the second microglia response type, enriched for interferon response genes, remains unaffected. Our data indicate that ARMs are the converging point of multiple AD risk factors.

ORGANISM(S): Mus musculus

PROVIDER: GSE127892 | GEO | 2019/04/23

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

The major risk factors for Alzheimer’s disease: Age, Sex and Genes, modulate the microglia response to Aβ plaques (CDEP)

Project description:Microglia are involved in Alzheimer’s disease (AD) by adopting activated phenotypes. How ageing in the absence or presence of β-amyloid (Aβ) deposition in different brain areas affects this response and whether sex and AD risk genes are involved, remains however largely unknown. Here we analyzed the gene expression profiles of more than 10,000 individual microglia cells isolated from cortex and hippocampus of male and female AppNL-G-F at 4 different stages of Aβ deposition and in age-matched control mice. We demonstrate that microglia adopt two major activated states during normal aging and after exposure to amyloid plaques. One of the responses (activated response microglia, ARM) is enhanced in particular by amyloid plaques and is strongly enriched with AD risk genes. The ARM response is not homogeneous, as subgroups of microglia overexpressing MHC type II and tissue repair genes (Dkk2, Gpnmb, Spp1) are induced upon prolonged Aβ exposure. Microglia in female mice advance faster in the activation trajectories. Similar activated states were also found in a second AD model and in human brain. We demonstrate that abolishing the expression of Apoe, the major genetic risk factor for AD, impairs the establishment of ARMs, while the second microglia response type, enriched for interferon response genes, remains unaffected. Our data indicate that ARMs are the converging point of multiple AD risk factors.

2019-04-23 | GSE127884 | GEO

Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology

Project description:Polygenic risk scores have identified that genetic variants without genome-wide significance still add to the genetic risk of developing Alzheimer’s disease (AD). Whether and how subthreshold risk loci translate into relevant disease pathways, is unknown. We investigate here the involvement of AD risk variants in the transcriptional responses of two mouse models: APPswe/PS1L166P and Thy-TAU22. A unique gene expression module, highly enriched for AD risk genes, is specifically responsive to Aβ but not TAU pathology. We identify in this module 7 established AD risk genes (APOE, CLU, INPP5D, CD33, PLCG2, SPI1 and FCER1G) and 11 AD GWAS genes below the genome-wide significance threshold (GPC2, TREML2, SYK, GRN, SLC2A5, SAMSN1, PYDC1, HEXB, RRBP1, LYN and BLNK), that become significantly upregulated when exposed to Aβ. Single microglia sequencing confirms that Aβ, not TAU, pathology induces marked transcriptional changes in microglia, including increased proportions of activated microglia. We conclude that genetic risk of AD functionally translates into different microglia pathway responses to Aβ pathology, placing AD genetic risk downstream of the amyloid pathway but upstream of TAU pathology.

2020-01-14 | GSE142267 | GEO

Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology

2020-01-14 | GSE110741 | GEO

Distinct amyloid-b and tau associated microglia profiles in Alzheimer's disease

Project description:Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-b and intraneuronal hyperphosphorylated, tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-b and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-b plaques or both amyloid-b plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-b load and localized to amyloid-b plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with over tau pathology. This full characterization of human disease associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies.

2021-02-20 | GSE148822 | GEO

Beneficial effect of ACI-24 vaccination on microglial phenotypes in an amyloidosis mouse model

Project description:Amyloid-beta (Aβ) deposition is an initiating factor in Alzheimer´s disease (AD). Microglia are the brain immune cells that surround and phagocytose Aβ, but their phagocytic capacity declines in AD. This is in agreement with studies that associate AD risk loci with genes regulating phagocytic function. Immunotherapies are currently pursued as therapeutic strategies against AD and there are increased efforts to understand the role of the immune system in ameliorating AD pathology. Here, we evaluated the effect of the Aβ targeting ACI-24 vaccine in preventing the AD pathology in an amyloidosis mouse model. ACI-24 vaccination elicited a robust and sustained antibody response in APPPS1 mice with an accompanying reduction of Aβ plaque load, amyloid plaque-associated ApoE and dystrophic neurites as compared to non-vaccinated controls. Furthermore, plaque-associated microglia had the tendency to be more activated post vaccination. The lower Aβ plaque load triggered by vaccination with ACI-24 was in concordance with the bulk transcriptomic analysis that revealed a reduction in the expression of several disease-associated microglial signatures. Accordingly, plaque-distant microglia displayed a more ramified morphology, supporting beneficial effects of the vaccination on bulk microglial phenotypes. Our study demonstrates that administration of the Aβ targeting vaccine, ACI-24, triggers protective microglial responses that translate into a reduction of AD pathology suggesting its use as a safe and cost effective AD therapeutic intervention.

2023-01-09 | PXD038665 | Pride

Early amyloid-induced changes in microglia gene expression in APP/PS1 mice [scRNA-seq]

Project description:Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia, characterized by deposition of extracellular amyloid-beta (Aβ) aggregates and intraneuronal hyperphosphorylated Tau. Many AD risk genes, identified in genome-wide association studies (GWAS), are expressed in microglia, the innate immune cells of the central nervous system. Specific subtypes of microglia emerged in relation to AD pathology, such as disease-associated microglia (DAMs), which increased in number with age in amyloid mouse models and in human AD cases. However, the initial transcriptional changes in these microglia in response to amyloid are still unknown. Here, to determine early changes in microglia gene expression, hippocampal microglia from APPswe/PS1dE9 (APP/PS1) mice and wildtype littermates were isolated and analyzed by RNA sequencing (RNA-seq). By bulk RNA-seq, transcriptomic changes were detected in hippocampal microglia from 6-months-old APP/PS1 mice. By performing single cell RNA-seq of CD11c-positive and negative microglia from 6-months-old APP/PS1 mice and analysis of the transcriptional trajectory from homeostatic to CD11c-positive microglia, we identified a set of genes that potentally reflect the initial response of microglia to Aβ.

2024-04-01 | GSE226938 | GEO

Early amyloid-induced changes in microglia gene expression in APP/PS1 mice [bulk RNA-seq]

2024-04-01 | GSE226937 | GEO

Microglia-mediated T cell Infiltration Drives Neurodegeneration in Tauopathy

Project description:Extracellular amyloid-β (Aβ) deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles (NFT) are two of the characteristic hallmarks in Alzheimer’s disease (AD). The regional progression of brain atrophy in AD highly correlates with tau accumulation but not amyloid deposition and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. To date, little is known about the extent or role of the adaptive immune response in the presence of Aβ or tau pathology. We systematically compared the immunological milieus in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not amyloid, developed a unique innate and adaptive immune response and that depletion of microglia or T-cells blocked tau-mediated neurodegeneration. T cells, especially cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the AD brain. T cell numbers correlated with the extent of neuronal loss, and dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of IFN-γ and PD-1signaling both significantly ameliorated brain atrophy. Our results thus reveal a tauopathy and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in AD and primary tauopathies.

2023-03-01 | GSE221856 | GEO

Reduced binding of apoE4 to complement factor H promotes amyloid-β oligomerization and neuroinflammation

Project description:Alzheimer’s disease (AD) is characterized by neuroinflammation, accumulation of amyloid-β (Aβ) plaques and neuronal degeneration in the brain. The APOE4 variant of apolipoprotein E (apoE) is the most prevalent genetic risk allele associated with late-onset AD. ApoE interacts with complement regulator factor H (FH) but the role of this interaction in AD pathogenesis is unknown.

2023-05-03 | GSE193513 | GEO

TREM2 Drives Microglia Response to Amyloid-β via SYK-dependent and -independent Paths [DAP12KI scRNA-seq]

Project description:Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer’s disease (AD). Microglia that adhere to Aβ plaques acquire a transcriptional signature, “diseaseassociated microglia” (DAM), which largely emanates from the TREM2-DAP12 receptor complex that transmits intracellular signals through the protein tyrosine kinase SYK. The human TREM2R47H variant associated with high AD risk fails to activate microglia via SYK. We found that SYK-deficient microglia cannot encase Aβ plaques, accelerating brain pathology and behavioral deficits. SYK deficiency impaired the PI3K-AKT-GSK3β-mTOR pathway, incapacitating anabolic support required for attaining the DAM profile. However, SYK-deficient microglia proliferated and advanced to an Apoe-expressing prodromal stage of DAM; this pathway relied on the adaptor DAP10, which also binds TREM2. Thus, microglial responses to Aβ involve non-redundant SYK- and DAP10-pathways. Systemic administration of an antibody against CLEC7A, a receptor that directly activates SYK, rescued microglia activation in mice expressing the TREM2R47H allele, unveiling new options for AD immunotherapy.

2022-10-10 | GSE210257 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data