RT Journal Article
SR Electronic
T1 PSEN1<sup>M146V</sup> and PSEN1<sup>A246E</sup> mutations associated with Alzheimer’s disease impair proper microglia differentiation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.10.08.561397
DO 10.1101/2023.10.08.561397
A1 Aubert, Antoine
A1 Mendoza-Ferri, Maria Grazia
A1 Bramoulle, Aude
A1 Stüder, François
A1 Colombo, Bruno Maria
A1 Mendoza-Parra, Marco Antonio
YR 2023
UL http://biorxiv.org/content/early/2023/10/10/2023.10.08.561397.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.