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Microglial MHC-I induction with aging and Alzheimer's is conserved in mouse models and humans
Collyn M Kellogg1,2, Kevin Pham1, Adeline H Machalinski1
1Genes and Human Disease Program, Oklahoma Medical Research Foundation, 825 NE 13Th Street, Oklahoma City, OK, USA.
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 Alzheimer's 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.
Insights
Microglia, not neurons, are the main source of Major histocompatibility complex I (MHC-I) in the brain. This immune molecule increases with aging and Alzheimer's disease, suggesting a role in brain health and disease.
Area of Science:
- Neuroimmunology
- Molecular Neuroscience
- Cellular Biology
Background:
- Major histocompatibility complex I (MHC-I) was previously thought to be absent in the central nervous system (CNS).
- MHC-I expression increases with brain aging in various species, but its cellular source remained unknown.
- Neuronal MHC-I is hypothesized to influence synapse elimination and Alzheimer's disease (AD) pathology.
Purpose of the Study:
- To determine the primary cell type responsible for MHC-I expression in the brain.
- To investigate the age-dependent changes in MHC-I expression and localization.
- To explore the potential role of MHC-I in neurodegeneration, particularly AD.
Main Methods:
- Ribosomal profiling, cell sorting, and single-cell RNA sequencing were used to analyze MHC-I expression.
- Translating ribosome affinity purification-quantitative PCR (TRAP-qPCR) quantified MHC-I pathway gene expression in specific cell types.
- Immunohistochemistry and protein analysis assessed MHC-I protein levels and localization in aging mice and human samples.
Main Results:
- Microglia were identified as the predominant source of both classical and non-classical MHC-I in mice and humans.
- Age-related increases in MHC-I pathway gene expression were observed in microglia, but not in astrocytes or neurons.
- MHC-I protein levels increased with age, particularly in microglia, and were elevated in AD models and human AD brains.
- Expression of MHC-I-binding receptors (Lilrs and Pilrs) in microglia also increased with aging and in AD.
Conclusions:
- Microglia are the primary producers of MHC-I in the brain, challenging previous assumptions.
- The age- and disease-associated increase in microglial MHC-I suggests a role in neuroinflammation and neurodegeneration.
- Cell-autonomous MHC-I signaling in microglia may regulate their function in aging and Alzheimer's disease.
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