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

Kellogg, C. M.; Pham, K.; Machalinski, A. H.; Blankenship, H. E.; Porter, H. L.; Stout, M. B.; Rice, H. C.; Sharpe, A. L.; Beckstead, M. J.; Elliott, A. J. C.; Ocanas, S. R.; Freeman, W. M.

doi:10.1101/2023.03.07.531435

bioRxiv · 10.1101/2023.03.07.531435

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

Kellogg, C. M.·Pham, K.·Machalinski, A. H.·Blankenship, H. E.·Porter, H. L.·Stout, M. B.·Rice, H. C.·Sharpe, A. L.·Beckstead, M. J.·Elliott, A. J. C.·Ocanas, S. R.·Freeman, W. M.

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Abstract

Major Histocompatibility Complex I (MHC-I) CNS cellular localization and function is still being determined after previously being thought to be absent from the brain. MHC-I expression has been reported to increase with brain aging in mouse, rat, and human whole tissue analyses but the cellular localization was undetermined. Neuronal MHC-I is proposed to regulate developmental synapse elimination and tau pathology in Alzheimers disease (AD). Here we report that across newly generated and publicly available ribosomal profiling, cell sorting, and single-cell data, microglia are the primary source of classical and non-classical MHC-I in mice and humans. Translating Ribosome Affinity Purification-qPCR analysis of 3-6 and 18-22 month old (m.o.) mice revealed significant age-related microglial induction of MHC-I pathway genes B2m, H2-D1, H2-K1, H2-M3, H2-Q6, and Tap1 but not in astrocytes and neurons. Across a timecourse (12-23 m.o.), microglial MHC-I gradually increased until 21 m.o. and then accelerated. MHC-I protein was enriched in microglia and increased with aging. Microglial expression, and absence in astrocytes and neurons, of MHC-I binding Leukocyte Immunoglobulin-like (Lilrs) and Paired immunoglobin-like type 2 (Pilrs) receptor families could enable cell-autonomous MHC-I signaling and increased with aging in mice and humans. Increased microglial MHC-I, Lilrs, and Pilrs were observed in multiple AD mouse models and human AD data across methods and studies. MHC-I expression correlated with p16INK4A, suggesting an association with cellular senescence. Conserved induction of MHC-I, Lilrs, and Pilrs with aging and AD opens the possibility of cell-autonomous MHC-I signaling to regulate microglial reactivation with aging and neurodegeneration.

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Kellogg, C. M., Pham, K., Machalinski, A. H., Blankenship, H. E., Porter, H. L., Stout, M. B., Rice, H. C., Sharpe, A. L., Beckstead, M. J., Elliott, A. J. C., Ocanas, S. R., Freeman, W. M.. 2023-03-10. Microglial MHC-I induction with aging and Alzheimer's is conserved in mouse models and humans. https://doi.org/10.1101/2023.03.07.531435

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