Cholesterol-dependent γ-secretase activity in buoyant cholesterol-rich membrane microdomains

Suzanne Wahrle, Pritam Das, Andrew C. Nyborg, Chris McLendon, Mikio Shoji, Takeshi Kawarabayashi, Linda H. Younkin, Steven G. Younkin, Todd E. Golde

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327 Scopus citations

Abstract

Buoyant membrane fractions containing presenilin 1 (PS1), an essential component of the γ-secretase complex, and APP CTFβ, a γ-secretase substrate, can be isolated from cultured cells and brain by several different fractionation procedures that are compatible with in vitro γ-secretase assays. Analysis of these gradients for amyloid β protein (Aβ) and CTFγ production indicated that γ-secretase activity is predominantly localized in these buoyant membrane microdomains. Consistent with this localization, we find that γ-secretase activity is cholesterol dependent. Depletion of membrane cholesterol completely inhibits γ-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 Aβ within cholesterol rich membrane microdomains.

Original languageEnglish (US)
Pages (from-to)11-23
Number of pages13
JournalNeurobiology of Disease
Volume9
Issue number1
DOIs
StatePublished - Jan 1 2002

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Keywords

  • Alzheimer's disease
  • Cholesterol
  • Lipid raft
  • Presenilin
  • γ-secretase

ASJC Scopus subject areas

  • Neurology

Cite this

Wahrle, S., Das, P., Nyborg, A. C., McLendon, C., Shoji, M., Kawarabayashi, T., Younkin, L. H., Younkin, S. G., & Golde, T. E. (2002). Cholesterol-dependent γ-secretase activity in buoyant cholesterol-rich membrane microdomains. Neurobiology of Disease, 9(1), 11-23. https://doi.org/10.1006/nbdi.2001.0470