Abstract
In Alzheimer’s disease (AD), amyloid-β (Aβ) is thought to be of neuronal origin. However, in single-cell RNAseq datasets from mouse and human, we found transcripts of amyloid precursor protein (APP) and the amyloidogenic-processing machinery equally abundant in oligodendrocytes (OLs). By cell-type-specific deletion of Bace1 in a humanized knock-in AD model,APPNLGF, we demonstrate that almost a third of cortical Aβ deposited in plaques is derived from OLs. However, excitatory projection neurons must provide a threshold level of Aβ production for plaque deposition to occur and for oligodendroglial Aβ to co-aggregate. Indeed, very few plaques are deposited in the absence of neuronally-derived Aβ, although soluble Aβ species are readily detected, especially in subcortical white matter. Our data identify OLs as a source of Aβ in vivo and further underscore a non-linear relationship between cellular Aβ production and resulting plaque formation. Ultimately, our observations are relevant for therapeutic strategies aimed at disease prevention in AD.
Publisher
Cold Spring Harbor Laboratory
Cited by
2 articles.
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