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

Area of Science:

• Neuroimmunology
• Cellular and Molecular Neuroscience
• Aging Research

Background:

• Major Histocompatibility Complex I (MHC-I) was previously thought to be absent in the central nervous system (CNS), but its expression increases with brain aging.
• The precise cellular localization and functional role of MHC-I in the brain, particularly in aging and neurodegenerative diseases like Alzheimer's disease (AD), remain unclear.
• Neuronal MHC-I has been implicated in synapse elimination and tau pathology in AD.

Approach:

• Utilized ribosomal profiling, cell sorting, and single-cell data to determine MHC-I cellular localization in mice and humans.
• Performed Translating Ribosome Affinity Purification-qPCR on mice of different ages (3-6 and 18-22 months) to analyze MHC-I pathway gene expression in microglia, astrocytes, and neurons.
• Quantified MHC-I protein levels and assessed the expression of MHC-I binding receptors (Lilrs and Pilrs) in aging mice and human AD data.

Key Points:

• Microglia are identified as the primary source of both classical and non-classical MHC-I in the brain of mice and humans.
• Age-related induction of MHC-I pathway genes (e.g., B2m, H2-D1, H2-K1, H2-M3, H2-Q6, Tap1) was observed in microglia but not in astrocytes or neurons.
• Microglial MHC-I expression and protein levels gradually increased with aging, accelerating after 21 months.
• Expression of MHC-I binding receptors, Leukocyte Immunoglobulin-like (Lilrs) and Paired immunoglobin-like type 2 (Pilrs), was enriched in microglia and increased with aging.
• Elevated microglial MHC-I, Lilrs, and Pilrs were consistently found in multiple AD mouse models and human AD datasets.
• MHC-I expression correlated with p16INK4A, indicating a potential association with cellular senescence.

Conclusions:

• Microglia, rather than neurons or astrocytes, are the principal producers of MHC-I in the aging and diseased brain.
• The conserved upregulation of MHC-I, Lilrs, and Pilrs during aging and in AD suggests a critical role for cell-autonomous microglial MHC-I signaling.
• This signaling pathway may regulate microglial reactivation, contributing to neuroinflammation and neurodegeneration in aging and AD.