Oligodendrocytes produce amyloid-β and contribute to plaque formation alongside neurons in Alzheimer's disease model mice

Nat Neurosci. 2024 Sep;27(9):1668-1674. doi: 10.1038/s41593-024-01730-3. Epub 2024 Aug 5.

Abstract

Amyloid-β (Aβ) is thought to be neuronally derived in Alzheimer's disease (AD). However, transcripts of amyloid precursor protein (APP) and amyloidogenic enzymes are equally abundant in oligodendrocytes (OLs). By cell-type-specific deletion of Bace1 in a humanized knock-in AD model, APPNLGF, we demonstrate that OLs and neurons contribute to Aβ plaque burden. For rapid plaque seeding, excitatory projection neurons must provide a threshold level of Aβ. Ultimately, our findings are relevant for AD prevention and therapeutic strategies.

MeSH terms

  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / metabolism
  • Alzheimer Disease* / pathology
  • Amyloid Precursor Protein Secretases* / metabolism
  • Amyloid beta-Peptides* / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Aspartic Acid Endopeptidases* / metabolism
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Transgenic
  • Neurons* / metabolism
  • Neurons* / pathology
  • Oligodendroglia* / metabolism
  • Oligodendroglia* / pathology
  • Plaque, Amyloid* / metabolism
  • Plaque, Amyloid* / pathology

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse