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- W4387491013 abstract "ABSTRACT Genetic variants associated with the late onset of Alzheimer’s disease (AD), were correlated with genes known to be expressed in microglia, suggesting for an AD-genetic component directly influencing microglia behavior. Instead, the role of the familial AD (fAD) genetic mutations was systematically studied from the angle of the Amyloid-Beta pathway; leaving their participation in microglia homeostasis unexplored. Here we demonstrate that two previously described fAD-related PSEN1 mutations directly impair proper microglia differentiation. While human induced pluripotent stem cells harboring the PSEN1-M146V mutation did not give rise to hematopoietic precursor (HPC) intermediate during microglia differentiation, a PSEN1-A246E mutant line managed to produce HPCs, but died within the first days of microglia differentiation. Detailed transcriptomics/epigenomics and functional assays revealed the setup of a pro-apoptotic program in the PSEN1-A246E mutant, which was circumvented when HPCs were grafted in brain organoids (BORGs). Microglia obtained in BORGs presented preferentially pro-inflammatory signatures, further supported by their correlation with recent data providing a detailed stratification of the various microglia populations within AD-patient samples. Overall, this study contributes to reconsider the influence of the previously identified familial mutations in the homeostasis of this immune component of the central nervous system." @default.
- W4387491013 created "2023-10-11" @default.
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- W4387491013 date "2023-10-10" @default.
- W4387491013 modified "2023-10-16" @default.
- W4387491013 title "PSEN1-M146V and PSEN1-A246E mutations associated with Alzheimers disease impair proper microglia differentiation" @default.
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- W4387491013 doi "https://doi.org/10.1101/2023.10.08.561397" @default.
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