Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer’s disease

Autor: Maxine Nelson, Yadong Huang, Seo Yeon Yoon, Dah-Eun J Amornkul, Kelly A. Zalocusky, Alice An, Antara Rao, Nicole Koutsodendris, Olga Cisne-Thomson, Jason Bant, David A. Bennett, Qin Xu, Yanxia Hao, Ramsey Najm, Alice Taubes
Rok vydání: 2021
Předmět:
Male
0301 basic medicine
Apolipoprotein E
Aging
Gene Expression
Neurodegenerative
Alzheimer's Disease
Transgenic
Mice
0302 clinical medicine
Databases
Genetic
Gene expression
80 and over
2.1 Biological and endogenous factors
Psychology
Gene Knock-In Techniques
Aetiology
Cells
Cultured
Aged
80 and over
Neurons
Cultured
biology
General Neuroscience
Neurodegeneration
Up-Regulation
Neurological
Female
Cognitive Sciences
Cells
Transgene
Neurogenetics
Mice
Transgenic
Major histocompatibility complex
Databases
03 medical and health sciences
Apolipoproteins E
Immune system
Genetic
Alzheimer Disease
MHC class I
Acquired Cognitive Impairment
Genetics
medicine
Animals
Humans
Aged
Neurology & Neurosurgery
Histocompatibility Antigens Class I
Neurosciences
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)
medicine.disease
Brain Disorders
030104 developmental biology
nervous system
Nerve Degeneration
biology.protein
Dementia
Neuroscience
030217 neurology & neurosurgery
Zdroj: Nature neuroscience, vol 24, iss 6
ISSN: 1546-1726
1097-6256
DOI: 10.1038/s41593-021-00851-3
Popis: 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.
Databáze: OpenAIRE
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