Oligodendrocytes and neurons contribute to amyloid-β deposition in Alzheimer's disease

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. ### Competing Interest Statement The authors have declared no competing interest.