CNS infiltration by Tet2-mutant peripheral myeloid cells protects from Alzheimer’s Disease

Microglia play a key role in Alzheimer’s disease (AD) pathogenesis by clearing damaged cells and misfolded proteins such as b-amyloid. In a mouse transplant model of AD, we identified a population of bone marrow-derived immune cells that had infiltrated the brain and taken on microglia characteristics. The percentage of these infiltrating microglia-like cells within the brain was increased in AD mice that were transplanted with Tet2-mutant bone marrow when compared to mice transplanted with either wildtype or Dnmt3a-mutant bone marrow following LPS treatment. We explored the effect of mutation of TET2 and DNMT3A in human induced microglial-like cells (iMGLs) and found that TET2-mutant iMGLs were more phagocytic and hyperinflammatory than DNMT3A-mutant or wildtype iMGLs. Bulk RNA sequencing of iMGLs confirmed the upregulation of phagocytic pathways in TET2-mutant iMGLs compared to DNMT3A-mutant or wildtype iMGLs. Bulk RNA sequencing of WT, TET2-mutant, and DNMT3A-mutant human induced microglial-like cells (iMGLs) that were either untreated or treated with 100ng/mL LPS for 24 hours. iMGLs were differentiated from isogenic human induced pluripotent stem cell (iPSC) lines that were CRISPR/Cas9 edited to harbor either DNMT3AR882H/WT or TET2DelE3-E11/WT mutations.