Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts
By R. Ehehalt, P. Keller, Christian Haass, C. Thiele, K. Simons. Journal of Cell Biology, 2003
1,148 citations recorded by the source corpus.
Formation of senile plaques containing the β-amyloid peptide (Aβ) derived from the amyloid precursor protein (APP) is an invariant feature of Alzheimer's disease (AD). APP is cleaved either by β-secretase or by α-secretase to initiate amyloidogenic (release of Aβ) 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 Aβ generation. Reducing cholesterol levels in N2a cells decreased Aβ production. APP and the β-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 Aβ in a cholesterol-dependent manner. Aβ generation was dependent on endocytosis and was reduced after expression of the dynamin mutant K44A and the Rab5 GTPase-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 β-secretase, APP outside rafts undergoes cleavage by α-secretase. Thus, access of α- and β-secretase to APP, and therefore Aβ generation, may be determined by dynamic interactions of APP with lipid rafts.
Subfields: Cell Biology, Molecular Biology, Physiology
View Paper: https://www.semanticscholar.org/paper/064a6181ce5a0b1142347401a4817123e5df71a0
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Cell Biology
In Molecular Biology
In Physiology
- Philip C. Wong
- Richard O'Brien
- T. Bird
- Christian Haass
- Sangram S. Sisodia
- G. Thinakaran
- C. Kaether
- D. Holtzman
Citations in the corpus
- Trafficking and proteolytic processing of APP. (2012, background): “Rafts are discussed as potential sites for efficient Ab generation, as APP and BACE1 apparently come into immediate contact within this compartment (Ehehalt et al. 2003; Abad- 12 Cite this article as Cold Spring Harb Perspect Med 2012;2:a006270 w w w .p e rs p e c ti v e si n m e d ic in e .o…”
- Linking Lipids to Alzheimer’s Disease: Cholesterol and Beyond (2011, background): “Tau phosphorylation by cdk5 and Fyn in response to amyloid peptide Aβ (25-35): involvement of lipid rafts.”
- Upregulated function of mitochondria-associated ER membranes in Alzheimer disease (2012, positive): “Analysis of the cells for duramycin sensitivity confirmed the biochemical findings, especially in the Ps1/2-DKO cells, where knockdown of Mfn2 blunted the increase in Dura sensitivity relative to that in WT MEFs (Figure 9C).”
- Amyloid Precursor Protein Processing and Alzheimer’s Disease (2011, background): “Why some surface APP is internalized into endosomes and some proteolyzed directly by α-secretase is unclear, although segregation of APP and BACE1 into lipid rafts may be a crucial element (Ehehalt et al. 2003).”