PSEN1-M146V and PSEN1-A246E mutations associated with Alzheimers disease impair proper microglia differentiation

Genetic variants associated with the late onset of Alzheimers 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.