Journal
NEURON
Volume 58, Issue 1, Pages 42-51Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2008.02.003
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Funding
- NIA NIH HHS [K01 AG029524-01A1, AG13956, R37 AG013956, AG029524, R01 AG027924, K01 AG029524, AG027924, R01 AG013956] Funding Source: Medline
- NIDA NIH HHS [DA07261, T32 DA007261] Funding Source: Medline
- NIMH NIH HHS [MH78823, R01 MH078823] Funding Source: Medline
- NINDS NIH HHS [P30 NS057105, R01 NS054174, NS54174] Funding Source: Medline
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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.
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