Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer's disease.
Kelly A ZalocuskyRamsey NajmAlice L TaubesYanxia HaoSeo Yeon YoonNicole KoutsodendrisMaxine R NelsonAntara RaoDavid A BennettJason BantDah-Eun J AmornkulQin XuAlice AnOlga Cisne-ThomsonYadong HuangPublished in: Nature neuroscience (2021)
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.
Keyphrases
- poor prognosis
- cognitive decline
- high fat diet
- immune response
- binding protein
- single cell
- wild type
- long non coding rna
- gene expression
- dna methylation
- mesenchymal stem cells
- adipose tissue
- human immunodeficiency virus
- inflammatory response
- hiv infected
- toll like receptor
- men who have sex with men
- insulin resistance