Neuronal ApoE Upregulates MHC-I Expression to Drive Selective Neurodegeneration in Alzheimer’s Disease
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ABSTRACT:
PROVIDER: PRJNA704819 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13782600.fastq.gz | Fastqsanger.gz | |||
| SRR13782601.fastq.gz | Fastqsanger.gz | |||
| SRR13782602.fastq.gz | Fastqsanger.gz | |||
| SRR13782603.fastq.gz | Fastqsanger.gz | |||
| SRR13782604.fastq.gz | Fastqsanger.gz |
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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, whereas 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 wild-type mice, human ApoE knock-in mice and humans with or without AD. Elimination or over-expression of neuronal ApoE revealed a causal relationship among 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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