Microglia-mediated protection against Alzheimer's disease pathology and detrimental effects in white matter revealed by Ptpn6 deletion.

Genetic variants affecting microglia can cause early-onset neurodegeneration or elevate Alzheimer's disease risk. To nominate regulators of relevant signaling pathways, we developed a genome-wide CRISPR screen in primary macrophages focused on survival. We identified Ptpn6, which encodes the inhibitory phosphatase SHP-1, as a crucial regulator for macrophage survival under reduced CSF1R signaling conditions in vitro. Deletion of Ptpn6 from adult microglia in vivo enhanced survival and decreased neuritic dystrophy around amyloid plaques in the TauPS2APP model of Alzheimer's disease. However, deletion also dysregulated homeostasis in normal white matter and exacerbated neurodegeneration in disease. Heterozygous deletion revealed a differential gene-dosage sensitivity for beneficial and detrimental effects, exhibiting reduced neuritic damage near plaques without white-matter harm. Single-cell RNA sequencing uncovered multiple disease-associated microglia (DAM)-like transcriptional states, with Lgals3+ microglia emerging alongside neurodegeneration after Ptpn6 deletion. In all, these findings reveal both the protective and latent degenerative potential of microglia held in check by Ptpn6.