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- W4210303553 abstract "Microglia-mediated neuroinflammation is hypothesized to contribute to disease progression in neurodegenerative diseases such as Alzheimer's Disease (AD). Recent single-cell RNA-seq studies highlight the heterogeneity of microglial subtypes. Since microglia are a relatively small proportion of CNS cells, standard single-cell omics approaches do not fully capture the diversity of microglia in human subjects. Understanding the gene expression and regulatory networks which define the spectrum of microglia phenotypes is critical to identifying specific targets for neuroinflammation modulating therapies.Our study utilized post-mortem brain tissue from 22 total (7 male) participants with an average age of 86.23 years and post-mortem interval of 5.42 hours. Of those individuals, 12 (3 male) had significant AD neuropathic change present in their brains upon postmortem analysis. Nuclei isolated from prefrontal cortex were sorted for PU.1 expression using fluorescence activated nucleus sorting (FANS). The FANS approach yields larger numbers of nuclei annotated as microglia with high quality sequence from each individual. We performed single-nucleus RNA-seq using the 10X Genomics Chromium platform.We isolated more than 4,000 microglia nuclei from each of the 22 participants, facilitating the comparison of profiles at an individual level in addition to group comparisons based on disease state. Unbiased clustering revealed 8 microglia clusters and improved resolution of microglia heterogeneity compared to standard single-cell approaches. Previously identified mouse disease-associated microglia (DAM) genes are not located in a single cluster of human microglia. DAM genes are also present in control aged brains. We identify clusters of microglia enriched for biological pathways implicating defined myeloid roles including a cluster of interferon-stimulated microglia as well as a cluster of autophagic/phagocytic microglia. In many, but not all, of our annotated clusters, including that with high expression of homeostatic genes, individuals with AD have greater enrichment of inflammatory pathways using pseudobulk analysis.We demonstrate significant heterogeneity in microglia subtypes in human brain. Regulation of expression in inflammation-related networks is detected in microglia from both control and AD individuals, though enrichment of specific inflammatory pathways differs. This is important as the field looks to target microglia mechanisms for pharmacological intervention while limiting off-target effects." @default.
- W4210303553 created "2022-02-08" @default.
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- W4210303553 date "2021-12-01" @default.
- W4210303553 modified "2023-09-26" @default.
- W4210303553 title "Microglia across the spectrum from homeostatic to disease phenotypes display enhanced inflammatory responses in human postmortem AD brain." @default.
- W4210303553 doi "https://doi.org/10.1002/alz.057792" @default.
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- W4210303553 hasPublicationYear "2021" @default.
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