Endocytosis is required for synaptic activity-dependent release of amyloid-β in vivo

Aggregation of amyloid-beta (A beta) peptide into soluble and insoluble forms within the brain extracellular space is central to the pathogenesis of Alzheimer's disease. Full-length amyloid precursor protein (APP) is endocytosed from the cell surface into endosomes where it is cleaved to produce A beta. A beta is subsequently released into the brain interstitial fluid (ISF). We hypothesized that synaptic transmission results in more APP endocytosis, thereby increasing A beta generation and release into the ISF. We found that inhibition of clathrin-mediated endocytosis immediately lowers ISF A beta levels in vivo. Two distinct methods that increased synaptic transmission resulted in an elevation of ISF A beta levels. Inhibition of endocytosis, however, prevented the activity-dependent increase in A beta. We estimate that similar to 70% of ISF A beta arises from endocytosis-associated mechanisms, with the vast majority of this pool also dependent on synaptic activity. These findings have implications for AD pathogenesis and may provide insights into therapeutic intervention.