Abstract Oligodendrocyte precursor cells (OPCs) shape brain function through intricate regulatory mechanisms. Here, we observed that OPC processes establish connections with neuronal somata, with smaller lysosomes positioned near these contact sites. Tracking lysosomes demonstrated neuronal lysosomes were attracted to and released at these contact points, eventually becoming incorporated into OPC processes, suggesting a selective, OPC-evoked release of lysosomes from neuronal soma and their ingestion by OPCs, highlighting a unique lysosome-mediated communication between neurons and OPCs. Diminished branching of OPC processes resulted in fewer neuron-OPC contacts, fostering larger lysosome accumulation in neurons, altered neuronal activity and escalated prevalence of senescent neurons during aging. A similar reduction in OPC branching and neuronal lysosome accumulation was evident in an early-stage Alzheimer’s disease mouse model. Together, these findings underscore the pivotal role of OPC processes in modulating neuronal activity through direct somatic contact and lysosome ingestion, presenting a prospective therapeutic avenue for addressing neurodegenerative diseases.

Neuronal lysosome transfer to oligodendrocyte precursor cells: a novel mechanism of neuron-glia communication and its role in neurodegenerative diseases