Microglia use TAM receptors to detect and engulf amyloid beta plaques
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA673444 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12954250.fastq.gz | Fastqsanger.gz | |||
| SRR12954251.fastq.gz | Fastqsanger.gz | |||
| SRR12954252.fastq.gz | Fastqsanger.gz | |||
| SRR12954253.fastq.gz | Fastqsanger.gz | |||
| SRR12954254.fastq.gz | Fastqsanger.gz |
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Project description:Two microglial TAM receptor tyrosine kinases - Axl and Mer - have been linked to Alzheimer’s disease, but their roles in disease have not been tested experimentally. We find that in Alzheimer’s disease and its mouse models, induced expression of Axl and Mer in amyloid plaque-associated microglia is coupled to induced plaque decoration by the TAM ligand Gas6 and its co-ligand phosphatidylserine. In the APP/PS1 mouse model of Alzheimer’s disease, sIngle cell RNAseq analysis comparing wild type microglia with those with Axl and Mer deficiency reveals a similar disease state transitional program of microglia but a dampened differential expression of numerous AD siganture genes in microglia lacking TAM receptors. In line with the transcriptomic data, using two-photon microscopy, we show that genetic ablation of Axl and Mer results in microglia that are unable to normally detect, respond to, organize, or phagocytose amyloid beta plaques. These major deficits notwithstanding, and contrary to expectation, TAM-deficient APP/PS1 mice develop fewer dense-core plaques than APP/PS1 mice with normal microglia. Our findings reveal that the TAM system is an essential mediator of microglial recognition and engulfment of amyloid plaques, and that TAM-driven microglial phagocytosis does not constrain, but rather promotes, plaque development.
2021-02-25 | GSE160523 | GEO
Project description:Two microglial TAM receptor tyrosine kinases, Axl and Mer, have been linked to Alzheimer's disease, but their roles in disease have not been tested experimentally. We find that in Alzheimer's disease and its mouse models, induced expression of Axl and Mer in amyloid plaque-associated microglia was coupled to induced plaque decoration by the TAM ligand Gas6 and its co-ligand phosphatidylserine. In the APP/PS1 mouse model of Alzheimer's disease, genetic ablation of Axl and Mer resulted in microglia that were unable to normally detect, respond to, organize or phagocytose amyloid-β plaques. These major deficits notwithstanding, TAM-deficient APP/PS1 mice developed fewer dense-core plaques than APP/PS1 mice with normal microglia. Our findings reveal that the TAM system is an essential mediator of microglial recognition and engulfment of amyloid plaques and that TAM-driven microglial phagocytosis does not inhibit, but rather promotes, dense-core plaque development.
| S-EPMC8102389 | biostudies-literature
Project description:Microglia gravitate toward amyloid plaques surrounded by externalized phosphatidylserine via TREM2
| PRJNA911174 | ENA
Project description:Amyloid plaques (Aβ plaques) are one of the hallmarks of Alzheimer’s disease (AD). The main constituent of Aβ plaques is beta-amyloid peptides but a complex interplay of other infiltrating proteins also co-localizes. We focused on proteomic differences between Aβ plaques and adjacent control tissue in the transgenic mouse model of AD (APPPS1-21) and in similar regions from non-transgenic littermates. A microproteomic strategy included isolation of regions of interest by laser capture microdissection and analyzed by label-free liquid chromatography mass spectrometry. An in-solution digest protocol with a buffer containing an acid-labile surfactant was used to increase protein solubilization and protease efficiency.
2021-03-25 | PXD014274 | Pride
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
Project description:PLCG2 is Associated with the Inflammatory Response and is Induced by Amyloid Plaques in Alzheimer's Disease
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Project description:The purpose of this project was to compare whole genome expression in 5 transgenic mice with human genes for dementia that result in either plaques or tangle pathology to the expression in wild-type control mice and to each other at different stages of disease progression. Total RNA was obtained from hippocampus, cortex and cerebellum in four lines of ‘amyloid’ transgenic mice (mutant human APP and APP/PSEN1 genes) and ‘TAU’ transgenic mice (mutant human MAPT gene) as well as wild-type control mice at 8,16, 32 and 72 weeks
2014-12-24 | E-GEOD-64398 | biostudies-arrayexpress
Project description:Background: ABCA1 has recently been identified as a novel genetic risk factor for Alzheimer’s disease. The major known role of ABCA1 in the brain is to transfer lipids onto lipid poor APOE. Given that APOEε4 is the strongest genetic risk factor for developing late onset Alzheimer’s disease, this recent finding implicates the cholesterol homeostatic pathway in the onset/progression of Alzheimer’s disease. microRNAs (miRs) are small RNA species that negatively regulate expression of their target genes. ABCA1 is regulated by miR-33, and loss of this miR significantly increases protein levels of ABCA1 and increases the lipidation of APOE. However, it is unknown if loss of miR-33 and subsequent increase in ABCA1 protein levels ameliorates amyloid pathology. Methods: We generated miR-33+/+;APP/PS1 and miR-33-/-;APP/PS1 mice to determine changes in amyloid-beta (Aβ) peptides and amyloid plaque formation utilizing biochemical and histological analyses. In addition to amyloid pathology, we assessed if deletion of miR-33 altered the activation of glial cells in the brains of these mice. We utilized in vitro methods to determine if miR-33 alters the phagocytosis of Aβ aggregates. We utilized RNA-sequencing and mass spectrometry to identify the transcriptome and proteome regulation by miR-33 in the context of amyloid pathology. Results: Deletion of miR-33 dramatically reduces insoluble Aβ peptide levels and the deposition of amyloid plaques in APP/PS1 mice. In addition, we identified that astrocyte and microglial activation is markedly decreased in miR-33-/-;APP/PS1 mice through histological analyses. Intriguingly, we show that loss of miR-33 results in amyloid plaques that are more compact, potentially implicating enhanced microglial phagocytosis. We confirm in vitro that loss of miR-33 significantly increases microglial phagocytosis of Aβ aggregates. Our multi-omics analyses reveal that deletion of miR-33 regulates immune response in the context of amyloid pathology. Interestingly, we identified that WNT/Beta-catenin signaling is significantly upregulated in miR-33-/-;APP/PS1 mice. Conclusion: We confirm that the deletion of miR-33 increases APOE lipidation and significantly reduces amyloid pathology as well as glial activation in APP/PS1 mice. Our results agree with previous work identifying APOE lipidation as an important modulator of amyloid pathology. We show, for the first time, that loss of miR-33 increases the phagocytosis of Aβ by microglia. In total, we identify miR-33 as a promising target for the amelioration of amyloid pathology.
2024-09-30 | GSE235179 | GEO
Project description:To further analyze the change of microRNA(miRNA) between normal peritoneal macrophage(PEC) and TAM from early tumor(12 days after 4T1 cell injection) or TAM from late tumor(21 days after 4T1 cell injection) , we employed Agilent mouse microRNA microarray Rel 12.0 as a discovery platform to identify miRNAs Total RNA from peritoneal macrophage and TAM of early tumor (tumor formed for 12days after BALB/c mice injected wth 4T1 cell) or TAM of late tumor(tumor formed for 21days after BALB/c mice injected with 4T1 cell) were extracted and analyzed using Agilent mouse microRNA microarray platform, and changes of miRNA were screened out. Agilent mouse microRNA microarray is designed for the profiling of mouse miRNA .627 mouse miRNA and 39 mouse virus-related miRNA can be detected by our microRNA microarray.
2015-03-31 | E-GEOD-67408 | biostudies-arrayexpress
Project description:Microglia are essential to maintain brain homeostasis, but when dysregulated, exert pathogenic functions in Alzheimer’s disease (AD). Recent evidence has implicated senescent/dystrophic microglia in the pathological process of AD. Whether microglial senescence is a cause or consequence of AD pathogenesis however is unclear. Here we report that autophagy, a lysosomal degradation pathway, restricts cellular senescence of microglia and confer neuroprotection in AD mouse model. Autophagy-deficient microglia show hallmarks of cellular senescence evidenced by reduced proliferation, increased Cdkn1a/p21Cip, dystrophy, and typical secretory phenotype. While disease-associated microglia (DAM) surrounding amyloid plaques exhibit heightened autophagy, autophagy deficient, senescent microglia (SAM) disengage from and thus fail to limit the diffusive amyloid plaques, causing enhanced tau phosphorylation and neurotoxicity in AD model. Treatment of senolytic drugs removes senescent microglia and alleviates neuropathology. Our study demonstrates a causal role of autophagy impairment in microglial senescence and neurotoxicity and suggests therapeutic potential of senolytic treatment for AD.
2023-04-24 | GSE192964 | GEO