Article: Endocytosis Is Required for Synaptic Activity-Dependent Release of Amyloid- beta 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 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.