期刊
NATURE NEUROSCIENCE
卷 24, 期 6, 页码 786-798出版社
NATURE PORTFOLIO
DOI: 10.1038/s41593-021-00851-3
关键词
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资金
- National Institutes of Health (NIH) [R01AG048017, RF1AG055421, R01AG055682]
- National Institute on Aging [P30AG10161, R01AG15819, R01AG17917, R01AG36836, U01AG32984, U01AG46152, U01061356]
- Illinois Department of Public Health
- Translational Genomics Research Institute
- NIH [S10 RR028962]
- James B. Pendleton Charitable Trust
- RNA sequencing
Selective neurodegeneration is a critical causal factor in Alzheimer's disease, and a study has demonstrated a causal relationship between neuronal ApoE expression and MHC-I expression leading to tau pathology and selective neurodegeneration. The correlation between ApoE expression and immune response pathways suggests a mechanism for the vulnerability of certain neurons in Alzheimer's disease.
Selective neurodegeneration is a critical causal factor in Alzheimer's disease. Zalocusky et al. demonstrate a causal chain linking neuronal ApoE expression to MHC-I expression and, subsequently, to tau pathology and selective neurodegeneration. 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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