Impaired Macroautophagy in Oligodendrocyte Precursor Cells Exacerbates Aging-related Cognitive Deficits via a Senescence Associated Signaling

Abstract Aging drives cognitive decline in the adult brain with unclear mechanisms. Previously, oligodendrocyte precursor cells (OPCs), the source cells of myelin-forming cells in the central nervous system (CNS), have been linked to brain aging by their compromised differentiation and regeneration capability. Whether a myelination-independent function of OPCs is involved in brain aging remains unknown. In this study, we herein report a novel role of OPCs in brain aging via disrupting neuronal plasticity. Our results demonstrate that macroautophagy influx declines in aged OPCs, which results in the accumulation of senescent OPCs in aged brains. Senescent OPCs impair neuronal plasticity and exacerbate neurodegeneration via CCL3/5-CCR5 signaling, eventually leading to cognitive decline. Our study, for the first time, demonstrates a myelination-independent role of OPCs in brain aging and identifies that a declined autophagy in OPCs is a driver of aging-associated cognitive decline.