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

Bone marrow-derived peripheral immune cells have been found to infiltrate the brain in many neurodegenerative diseases, such as Alzheimer's disease (AD). Using a mouse transplant model of AD (5xFAD mice), we found that loss of the clonal hematopoiesis associated gene Tet2 within peripheral immune cells led to increased myeloid cell brain infiltration when compared to mice with either wildtype or Dnmt3a-mutant peripheral immune cells. scRNA-seq on either CD11a-enriched or CD45-enriched brain cells from 5xFAD mice transplanted with either wildtype, Tet2-/- or Dnmt3a-/- bone marrow, confirmed our finding that loss of Tet2 leads to increased peripheral myeloid cell brain infiltration in AD mice. scRNA-seq identified that the change in infiltrating peripheral immune cells was primarily attributed to increased M1 macrophages and non-classical monocytes in the brains of 5xFAD mice with Tet2-mutant bone marrow. We further identified the upregulation of chemotaxis and migration related pathways in Tet2-mutant infiltrating macrophages and monocytes when compared to wildtype or Dnmt3a-mutant infiltrating cells, providing a mechanism by which loss of Tet2 in peripheral immune cells leads to increased brain infiltration in an AD setting.