Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer’s disease
Open accessAbstract
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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Sample sizes for mouse snRNA-seq studies were determined by a power analysis based on effect sizes from previous studies and literature.
“Sample sizes for mouse snRNA-seq studies were determined by a power analysis based on effect sizes from our previous studies22,55 and literature.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [22]
The “Sample size, randomization, and blinding” section (page unavailable) says the authors chose four mice per condition after a literature search identified a field standard of at least three. It describes that basis for the mouse sample size, rather than a power analysis based on prior effect sizes. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAltered amyloid-β processing and DNA damage have been associated with APOE4 and Alzheimer's disease.
“Altered amyloid-β processing and DNA damage have been associated with APOE4 and AD19–21.”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [19]
The Abstract and Results report correlations between neuronal apoE expression and DNA-damage-and-repair pathways in an Alzheimer’s disease context, but do not establish that association specifically for APOE4. The passages do not support the other part of the claim, altered amyloid-β processing; the paper’s reported findings instead focus on MHC-I and Tau pathology. (LLM, conf=0.82)
Experimental — accuracy not yet measuredSome neurons and oligodendrocytes also express APOE.
“Some neurons and oligodendrocytes also express APOE”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [22]
Neurons have low expression of APOE under homeostatic conditions.
“Neurons have often been understudied in relation to the effects of APOE on metabolism due to their low expression of APOE under homeostatic conditions 36,37 .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [36]
The upregulation of class I MHC mediated antigen processing and presentation pathways in APOE4 iNeurons is consistent with a previous study.
“We also found an upregulation of class I MHC mediated antigen processing and presentation pathways in APOE4 iNeurons which is consistent with a previous study 36 .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [36]
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References 64 · Cited by 189
- Authors
- Zalocusky, K. A., Najm, R., Taubes, A. L., Hao, Y., Yoon, S. Y., Koutsodendris, N., Nelson, M. R., Rao, A., Bennett, D. A., Bant, J., Amornkul, D.-E. J., Xu, Q., An, A., Cisne-Thomson, O., & Huang, Y.
- Affiliations
- Gladstone Institutes (US)
- Rush University Medical Center (US)
- Corresponding author
- Zalocusky, Kelly A.
- Huang, Yadong
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2021-05-06
- Volume
- 24
- Issue
- 6
- Pages
- 786-798
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC9145692
- OpenAlex
- W3157602736
- Cited by
- 189
- References
- 64
- Citations by year
- 2026: 29 · 2025: 39 · 2024: 36 · 2023: 50 · 2022: 20 · 2021: 13
- FWCI
- 21.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (R01AG048017, RF1AG055421, R01AG055682)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, selective neurodegeneration, apolipoprotein E, MHC class I, tau pathology, APOE ε4, hippocampus, single-nucleus RNA sequencing, neuronal heterogeneity
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Animals, Apolipoproteins E, Cells, Cultured, Female, Humans, Male, Mice, Transgenic, Nerve Degeneration, Neurons, Histocompatibility Antigens Class I, Up-Regulation, Gene Expression, Databases, Genetic, Mice, Gene Knock-In Techniques
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