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

Nat Neurosci. 2021 Jun;24(6):786-798. doi: 10.1038/s41593-021-00851-3. Epub 2021 May 6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Animals
  • Apolipoproteins E / biosynthesis*
  • Apolipoproteins E / genetics
  • Cells, Cultured
  • Databases, Genetic / trends
  • Female
  • Gene Expression
  • Gene Knock-In Techniques / methods
  • Histocompatibility Antigens Class I / biosynthesis*
  • Histocompatibility Antigens Class I / genetics
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Neurons / metabolism*
  • Neurons / pathology
  • Up-Regulation / physiology*


  • Apolipoproteins E
  • Histocompatibility Antigens Class I