Endocytosis Is Required for Synaptic Activity-Dependent Release of Amyloid-[beta] In Vivo

Aggregation of amyloid-β (Aβ) 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 Aβ. A...

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Veröffentlicht in:Neuron (Cambridge, Mass.) Mass.), 2008-04, Vol.58 (1), p.42
Hauptverfasser: Cirrito, John R, Kang, Jae-Eun, Lee, Jiyeon, Stewart, Floy R, Verges, Deborah K, Silverio, Luz M, Bu, Guojun, Mennerick, Steven, Holtzman, David M
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container_issue 1
container_start_page 42
container_title Neuron (Cambridge, Mass.)
container_volume 58
creator Cirrito, John R
Kang, Jae-Eun
Lee, Jiyeon
Stewart, Floy R
Verges, Deborah K
Silverio, Luz M
Bu, Guojun
Mennerick, Steven
Holtzman, David M
description Aggregation of amyloid-β (Aβ) 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 Aβ. Aβ is subsequently released into the brain interstitial fluid (ISF). We hypothesized that synaptic transmission results in more APP endocytosis, thereby increasing Aβ generation and release into the ISF. We found that inhibition of clathrin-mediated endocytosis immediately lowers ISF Aβ levels in vivo. Two distinct methods that increased synaptic transmission resulted in an elevation of ISF Aβ levels. Inhibition of endocytosis, however, prevented the activity-dependent increase in Aβ. We estimate that ∼70% of ISF Aβ 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.
doi_str_mv 10.1016/j.neuron.2008.02.003
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subjects Alzheimer's disease
Cell culture
Electrodes
Endocytosis
Molecular weight
Neurons
Pathogenesis
Peptides
Proteins
Rodents
Statistical analysis
Transgenic animals
title Endocytosis Is Required for Synaptic Activity-Dependent Release of Amyloid-[beta] In Vivo
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