title: Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo.
abstract: Aggregation of amyloid-beta (Abeta) 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 Abeta. Abeta is subsequently released into the brain interstitial fluid (ISF). We hypothesized that synaptic transmission results in more APP endocytosis, thereby increasing Abeta generation and release into the ISF. We found that inhibition of clathrin-mediated endocytosis immediately lowers ISF Abeta levels in vivo. Two distinct methods that increased synaptic transmission resulted in an elevation of ISF Abeta levels. Inhibition of endocytosis, however, prevented the activity-dependent increase in Abeta. We estimate that approximately 70% of ISF Abeta 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.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. cirritoj@neuro.wustl.edu
authors.forename: John R
authors.initials: JR
authors.lastname: Cirrito
authors.forename: Jae-Eun
authors.initials: JE
authors.lastname: Kang
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Lee
authors.forename: Floy R
authors.initials: FR
authors.lastname: Stewart
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Verges
authors.forename: Luz M
authors.initials: LM
authors.lastname: Silverio
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.forename: Steven
authors.initials: S
authors.lastname: Mennerick
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D004705:Endocytosis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013569:Synapses / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides