Title: Loss of gamma-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, Freddy
Lütjohann, Dieter
Walter, Jochen # ×
Issue Date: 12-Nov-2008
Publisher: The Society for Neuroscience
Series Title: Journal of Neuroscience vol:28 issue:46 pages:12097-12106
Abstract: Presenilins (PSs) are components of the gamma-secretase complex that mediates intramembranous cleavage of type I membrane proteins. We show that gamma-secretase is involved in the regulation of cellular lipoprotein uptake. Loss of gamma-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 gamma-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.
ISSN: 0270-6474
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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