Microglial MHC-I induction with aging and Alzheimer’s is conserved in mouse models and humans

AbstractMajor Histocompatibility Complex I (MHC-I) function in the CNS is still being determined after previously being thought to be absent from the brain. MHC-I expression increases with brain aging in mouse, rat, and human whole tissue analyses. Neuronal MHC-I expression has been proposed to regulate developmental synapse elimination and tau pathology in Alzheimer’s disease (AD). However, the CNS cellular localization of MHC-I expression has been unclear. Across newly generated and publicly available ribosomal profiling, cell sorting, and single cell data, microglia were found to be the primary source of classical and non-classical MHC-I in mice and humans. TRAP-qPCR analysis of 3-6 m.o. and 18-22 m.o. mice revealed significant age-related induction of B2m, H2-D1, H2-K1, H2-M3, H2-Q6, and Tap1 in microglia but not in astrocytes and neurons. Across a timecourse from 12-23 m.o., microglial MHC-I gradually increases until 21 m.o. and then accelerates. MHC-I protein was also enriched in microglia and increased with aging. Expression of MHC-I binding Leukocyte Immunoglobulin-like (Lilr) and Paired immunoglobin-like type 2 (Pilr) receptors in microglia but not astrocytes or neurons opens the possibility of cell-autonomous signaling and are also increased with aging in mice and humans. Increased microglial MHC-I, Lilrs, and Pilrs were observed in mouse AD models and human data across numerous studies and in RNA-Seq of microglia from APP-PSEN1 mice. MHC-I expression occurred concurrently with p16 suggesting an association with cellular senescence. The conserved induction of MHC-I, Lilrs, and Pilrs with aging and AD open the possibility of cell-autonomous signaling to regulate microglial reactivation.