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Title: Regulation of cholesterol and sphingomyelin metabolism by amyloid-beta and presenilin
Authors: Grimm, Marcus O W
Grimm, Heike S
Pätzold, Andreas J
Zinser, Eva G
Halonen, Riikka
Duering, Marco
Tschäpe, Jakob A
De Strooper, Bart
Müller, Ulrike
Shen, Jie
Hartmann, Tobias # ×
Issue Date: Dec-2005
Publisher: Macmillan Magazines Ltd.
Series Title: Nature Cell Biology vol:7 issue:11 pages:1118-23
Abstract: Amyloid beta peptide (Abeta) has a key role in the pathological process of Alzheimer's disease (AD), but the physiological function of Abeta and of the amyloid precursor protein (APP) is unknown. Recently, it was shown that APP processing is sensitive to cholesterol and other lipids. Hydroxymethylglutaryl-CoA reductase (HMGR) and sphingomyelinases (SMases) are the main enzymes that regulate cholesterol biosynthesis and sphingomyelin (SM) levels, respectively. We show that control of cholesterol and SM metabolism involves APP processing. Abeta42 directly activates neutral SMase and downregulates SM levels, whereas Abeta40 reduces cholesterol de novo synthesis by inhibition of HMGR activity. This process strictly depends on gamma-secretase activity. In line with altered Abeta40/42 generation, pathological presenilin mutations result in increased cholesterol and decreased SM levels. Our results demonstrate a biological function for APP processing and also a functional basis for the link that has been observed between lipids and Alzheimer's disease (AD).
URI: 
ISSN: 1465-7392
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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