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

Wahrle, Suzanne, Das, Pritam, Nyborg, Andrew C., McLendon, Chris, Shoji, Mikio, Kawarabayashi, Takeshi, Younkin, Linda H., Younkin, Steven G., Golde, Todd E.·2002·Neurobiology of Disease
DOI 10.1006/nbdi.2001.0470
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Abstract

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.

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  • Aβ peptides are produced primarily by neurons via sequential cleavage of APP by β- and γ-secretases at lipid rafts in the plasma membrane.

    “Aβ peptides are produced primarily by neurons via the sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases (amyloidogenic pathway) at lipid rafts in the plasma membrane (PM) [35–37].”

    From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [37]

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Metadata

Authors
Wahrle, S., Das, P., Nyborg, A. C., McLendon, C., Shoji, M., Kawarabayashi, T., Younkin, L. H., Younkin, S. G., & Golde, T. E.
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2002-02
Volume
9
Issue
1
Pages
11-23
ISSN
0969-9961
DOI
10.1006/nbdi.2001.0470
Cited by
356
References
0
Language
en
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)

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