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

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

PROVIDER: PRJNA966986 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24422515_1.fastq.gz	Fastqsanger.gz
	SRR24422515_2.fastq.gz	Fastqsanger.gz
	SRR24422516_1.fastq.gz	Fastqsanger.gz
	SRR24422516_2.fastq.gz	Fastqsanger.gz
	SRR24422517_1.fastq.gz	Fastqsanger.gz

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

Project description: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. Neuronal MHC-I has been 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 were the primary source of classical and non-classical MHC-I in mice and humans. Translating Ribosome Affinity Purification (TRAP)-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 also 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 AD mouse models and human AD data is evident across numerous mouse models, 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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Project description:Selective neurodegeneration is a critical causal factor in Alzheimer’s disease (AD); however, the mechanisms that lead some neurons to perish while others remain resilient are unknown. We sought potential drivers of this selective vulnerability using single-nucleus RNA sequencing and discovered that apoE expression level is a substantial driver of neuronal variability. Strikingly, neuronal expression of apoE—which has a robust genetic linkage to AD—correlated strongly, on a cell-by-cell basis, with immune response pathways in neurons in the brains of wildtype mice, human apoE knock-in mice, and humans with or without AD. Elimination or over-expression of neuronal apoE revealed a causal relationship between apoE expression, neuronal MHC-I expression, Tau pathology, and neurodegeneration. Functional reduction of MHC-I ameliorated Tau pathology in apoE4-expressing primary neurons and in mouse hippocampi expressing pathological Tau. These findings suggest a mechanism linking neuronal apoE expression to MHC-I expression and, subsequently, to Tau pathology and selective neurodegeneration.

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