Cholesterol-Dependent γ-Secretase Activity in Buoyant Cholesterol-Rich Membrane Microdomains

Neurobiology of Disease, 2002

402 citations recorded by the source corpus.

Buoyant membrane fractions containing presenilin 1 (PS1), an essential component of the gamma-secretase complex, and APP CTFbeta, a gamma-secretase substrate, can be isolated from cultured cells and brain by several different fractionation procedures that are compatible with in vitro gamma-secretase assays. Analysis of these gradients for amyloid beta protein (Abeta) and CTFgamma production indicated that gamma-secretase activity is predominantly localized in these buoyant membrane microdomains. Consistent with this localization, we find that gamma-secretase activity is cholesterol dependent. Depletion of membrane cholesterol completely inhibits gamma-secretase cleavage, which can be restored by cholesterol replacement. Thus, altering cholesterol levels may influence the development of Alzheimer's disease (AD) by influencing production and deposition of Abeta within cholesterol rich membrane microdomains.

Subfields: Molecular Biology, Oncology, Physiology

View Paper: https://www.semanticscholar.org/paper/56ef7b6702bed89bf532dd5df2563aea837740d7

Citations in the corpus

• Calcium dyshomeostasis and intracellular signalling in alzheimer's disease (2002, neutral): “This might be for technical reasons: apart from presenilin, other proteins are required for γ-secretase activity, as well as a lipid-enriched environmen”
• Linking Lipids to Alzheimer’s Disease: Cholesterol and Beyond (2011, neutral): “Tau phosphorylation by cdk5 and Fyn in response to amyloid peptide Aβ (25-35): involvement of lipid rafts.”
• Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts (2003, neutral): “Also the -secretase complex was shown to be raft associated (Li et al., 2000; Wahrle et al., 2002).”