Upregulation Of App Endocytosis By Neuronal Aging Drives Amyloid-Dependent Synapse Loss

Neuronal aging increases the risk of late-onset Alzheimer's disease. During normal aging, synapses decline, and beta-amyloid (A beta) accumulates intraneuronally. However, little is known about the underlying cell biological mechanisms. We studied neuronal aging using normal-aged brain and aged mouse primary neurons that accumulate lysosomal lipofuscin and show synapse loss. We identified the upregulation of amyloid precursor protein (APP) endocytosis as a neuronal aging mechanism that potentiates APP processing and A beta production in vitro and in vivo. The increased APP endocytosis may contribute to the early endosome enlargement observed in the aged brain. Mechanistically, we showed that clathrin-dependent APP endocytosis requires F-actin and that clathrin and endocytic F-actin increase with neuronal aging. Finally, A beta production inhibition reverts synaptic decline in aged neurons, whereas A beta accumulation, promoted by endocytosis upregulation in younger neurons, recapitulates aging-related synapse decline. Overall, we identify APP endocytosis upregulation as a potential mechanism of neuronal aging and, thus, a novel target to prevent late-onset Alzheimer's disease.This article has an associated First Person interview with the first author of the paper.