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P4‐257: NEURONS WITH TAU AGGREGATES EXPOSE PHOSPHATIDYLSERINE AND ARE PHAGOCYTOSED LIVE BY MICROGLIA
Author(s) -
Brelstaff Jack H.,
Tolkovsky Aviva,
Ghetti Bernardino Francesco,
Goedert Michel,
Spillantini Maria Grazia
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.07.079
Subject(s) - microglia , phagocytosis , tauopathy , microbiology and biotechnology , programmed cell death , phosphatidylserine , biology , tau protein , chemistry , neurodegeneration , apoptosis , inflammation , immunology , pathology , biochemistry , medicine , alzheimer's disease , phospholipid , disease , membrane
historically held microglia phenotypes. These studies also pointed out that population level assessment ofmicroglia phenotype is insufficient to resolve the contribution of this cell type to neurodegenerative diseases. Methods: To explore human microglia phenotype diversity in an unbiased way, we performed high-throughput single cell RNA sequencing of isolatedmicroglia.Weprofiled15,910CD45+ cells isolated from the cerebral cortices of 7 aged (mean 92.5 years of age) and 8 middle-aged (mean 39.6 years of age) individuals. All aged donors had a non-zero burden of amyloid plaques and neurofibrillary tangles in their brain. Results:We have identified 14 distinct subpopulations of human microglia. When analyzing the interrelatedness of the clusters we found that the largest cluster (cluster number 1 containing 42.2% of the cells) was centrally positioned with all the other clusters "originating” from this central, "homeostatic” cluster. Each microglia subset had a unique set of surface markers and expressed a unique combination of transcription factors. We have confirmed the existence of these subpopulations in situwith immunohistochemistry. The transcriptomic signatures specific to the identifiedmicroglia subsets showed divergent association with neurodegenerative and neuroinflammatory diseases, such as multiple sclerosis and Alzheimer’s disease and had a unique relationship with the histopathological traits associated with Alzheimer’s disease and aging.Marker genes of the disease associatedmicroglia (DAM) phenotype, as well as other microglia signatures recently described inmouse, didnot segregate clearly to anyonehuman microglia subpopulation. Conclusions:Microglia in the human brain can acquire a multitude of phenotypic states, which are not well captured in mouse models. These unique human microglia subsets have distinct functional relevance in neurodegenerative diseases and aging. Accordingly our dataset offers novel insights into the involvement of microglia in these processes as well as provides new targets for biomarker and therapeutics development.