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  Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts

Ehehalt, R., Keller, P., Haass, C., Thiele, C., & Simons, K. (2003). Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. Journal of Cell Biology, 160(1), 113-123.

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 Creators:
Ehehalt, R.1, Author           
Keller, P.1, Author           
Haass, C., Author
Thiele, C.1, Author           
Simons, K.1, Author           
Affiliations:
1Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society, ou_2340692              

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Free keywords: lipid rafts; beta-amyloid; BACE; Alzheimer's disease; endocytosis
 Abstract: Formation of senile plaques containing the beta-amyloid peptide (Abeta) derived from the amyloid precursor protein (APP) is an invariant feature of Alzheimer's disease (AD). APP is cleaved either by beta-secretase or by alpha-secretase to initiate amyloidogenic (release of Abeta) or nonamyloidogenic processing of APP, respectively. A key to understanding AD is to unravel how access of these enzymes to APP is regulated. Here, we demonstrate that lipid rafts are critically involved in regulating Abeta generation. Reducing cholesterol levels in N2a cells decreased Abeta production. APP and the beta-site APP cleavage enzyme (BACE1) could be induced to copatch at the plasma membrane upon cross-linking with antibodies and to segregate away from nonraft markers. Antibody cross-linking dramatically increased production of Abeta in a cholesterol- dependent manner. Abeta generation was dependent on endocytosis and was reduced after expression of the dynamin mutant K44A and the Rab5 GTP se-activating protein, RN-tre. This inhibition could be overcome by antibody cross-linking. These observations suggest the existence of two APP pools. Although APP inside raft clusters seems to be cleaved by beta-secretase, APP outside rafts undergoes cleavage by alpha-secretase. Thus, access of alpha- and beta-secretase to APP, and therefore Abeta generation, may be determined by dynamic interactions of APP with lipid rafts.

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Language(s): eng - English
 Dates: 2003-01-06
 Publication Status: Issued
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 15645
ISI: 000180364400010
 Degree: -

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Title: Journal of Cell Biology
  Alternative Title : J. Cell Biol.
Source Genre: Journal
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Pages: - Volume / Issue: 160 (1) Sequence Number: - Start / End Page: 113 - 123 Identifier: ISSN: 0021-9525