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- Title
Loss of γ-Secretase Function Impairs Endocytosis of Lipoprotein Particles and Membrane Cholesterol Homeostasis.
- Authors
Tamboli, Irfan Y.; Prager, Kai; Thal, Dietmar R.; Thelen, Karin M.; Dewachter, Ilse; Pietrzik, Claus U.; St. George-Hyslop, Peter; Sisodia, Sangram S.; De Strooper, Bart; Heneka, Michael T.; Filippov, Mikhail A.; Müller, Ulrike; van Leuven, Fred; Lütjohann, Dieter; Walter, Jochen
- Abstract
Presenilins (PSs) are components of theγ-secretase complex that mediates intramembranous cleavage of type I membrane proteins. We show that γ-secretase is involved in the regulation of cellular lipoprotein uptake. Loss of γ-secretase function decreased endocytosis of low-density lipoprotein (LDL) receptor. The decreased uptake of lipoproteins led to upregulation of cellular cholesterol biosynthesis by increased expression of CYP51 and enhanced metabolism of lanosterol. Genetic deletion of PS1 or transgenic expression of PS1 mutants that cause early-onset Alzheimer's disease led to accumulation of γ-secretase substrates and mistargeting of adaptor proteins that regulate endocytosis of the LDL receptor. Consistent with decreased endocytosis of these receptors, PS1 mutant mice have elevated levels of apolipoprotein E in the brain. Thus, these data demonstrate a functional link between two major genetic factors that cause early-onset and late-onset Alzheimer's disease.
- Subjects
PRESENILINS; MEMBRANE proteins; BIOLOGICAL membranes; ION channels; LIPOPROTEINS
- Publication
Journal of Neuroscience, 2008, Vol 28, Issue 46, p12094
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.2635-08.2008