Impaired Macroautophagy in Oligodendrocyte Precursor Cells Suppresses Neuronal Plasticity via a Senescence Associated Signaling

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, 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 myelination-independent role of OPCs in exaggerating cognitive decline in the aging brain via suppressing neuronal plasticity. Our results demonstrate that macroautophagic flux declines in aged OPCs. Inactivation of autophagy promotes the senescence of OPCs, which activates CCL3/5-CCR5 signaling. Through this, autophagy-defective OPCs impair glutamatergic transmission, neuronal excitability, and long-term potentiation (LTP), exaggerating the cognitive decline in the aging brain. 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 pivotal factor in driving aging-associated cognitive decline.