Upregulation of APP endocytosis by neuronal aging drives amyloid-dependent synapse loss

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13 Citations (Scopus)


Neuronal aging increases the risk of late-onset Alzheimer’s disease. During normal aging, synapses decline, and β-amyloid (Aβ) 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 Aβ 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, Aβ production inhibition reverts synaptic decline in aged neurons, whereas Aβ 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.

Original languageEnglish
Article numberjcs255752
JournalJournal of Cell Science
Issue number9
Publication statusPublished - May 2021


  • Actin-dependent endocytosis
  • Alzheimer’s disease
  • APP endocytosis
  • Clathrin-mediated endocytosis
  • Neuronal aging
  • β-amyloid


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