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PMID: 18400162 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Neuron ·Vol. 58 ·No. 1 ·2008-04-10 ·Pages 42-51

Cirrito JR, Kang JE, Lee J, Stewart FR, Verges DK, Silverio LM, Bu G, Mennerick S, Holtzman DM

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.

MeSH Terms
Alzheimer Disease/etiology,metabolism,physiopathology Amyloid beta-Peptides/genetics,metabolism,physiology Animals Endocytosis/genetics Mice Mice, Inbred C57BL Mice, Transgenic Synapses/genetics,metabolism Synaptic Transmission/genetics
Chemicals
Amyloid beta-Peptides
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Cirrito John R
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. cirritoj@neuro.wustl.edu
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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Article Info
Journal
Neuron
Abbr.
Neuron
ISSN
1097-4199
DOI
10.1016/j.neuron.2008.02.003
Email
cirritoj@neuro.wustl.edu
Published
2008-04-10
Pages
42-51
Language
English
Region
United States
NLM ID
8809320
PMCID
PMC2390913
Subset
IM
Grants
NINDS NIH HHS · R01 NS054174 · United States
NIA NIH HHS · R01 AG013956 · United States
NIA NIH HHS · K01 AG029524-01A1 · United States
NIDA NIH HHS · DA07261 · United States
NIA NIH HHS · AG13956 · United States
NIA NIH HHS · R37 AG013956 · United States
NIDA NIH HHS · T32 DA007261 · United States
NIA NIH HHS · AG027924 · United States
NIMH NIH HHS · MH78823 · United States
NINDS NIH HHS · P30 NS057105 · United States
NIA NIH HHS · K01 AG029524 · United States
NIA NIH HHS · R01 AG027924 · United States
NIMH NIH HHS · R01 MH078823 · United States
NINDS NIH HHS · NS54174 · United States
NIA NIH HHS · AG029524 · United States
External Links
PubMed source DOI: 10.1016/j.neuron.2008.02.003 PMC Full Text View journal details
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