Single-cell RNA-sequencing identifies disease-associated oligodendrocytes in male APP NL-G-F and 5XFAD mice

Abstract

Alzheimer's disease (AD) is associated with progressive neuronal degeneration as amyloid-beta (A beta) and tau proteins accumulate in the brain. Glial cells were recently reported to play an important role in the development of AD. However, little is known about the role of oligodendrocytes in AD pathogenesis. Here, we describe a disease-associated subpopulation of oligodendrocytes that is present during progression of AD-like pathology in the male App(NL-G-F) and male 5xFAD AD mouse brains and in postmortem AD human brains using single-cell RNA sequencing analysis. Aberrant Erk1/2 signaling was found to be associated with the activation of disease-associated oligodendrocytes (DAOs) in male App(NL-G-F) mouse brains. Notably, inhibition of Erk1/2 signaling in DAOs rescued impaired axonal myelination and ameliorated A beta-associated pathologies and cognitive decline in the male App(NL-G-F) AD mouse model. Oligodendrocytes have been increasingly shown to be involved in Alzheimer's disease (AD). Here, the authors perform single-cell RNA-sequencing on APP NL-G-F mice and describe a disease-associated oligodendrocyte (DAO) population. They find inhibition of Erk1/2 signaling in DAOs rescues impaired axonal myelination and cognitive decline in an AD mouse model.