[en] 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.
Disciplines :
Neurology
Author, co-author :
Tamboli, Irfan Y; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Prager, Kai; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Thal, Dietmar R; Institute of Pathology, University of Ulm, 89081 Ulm, Germany
Thelen, Karin M; Department of Clinical Pharmacology, University of Bonn, 53127 Bonn, Germany
Dewachter, Ilse; Department of Human Genetics, Experimental Genetics Group, Katholieke Universiteit (K.U.) Leuven, 3000 Leuven, Belgium
Pietrzik, Claus U; Department of Physiological Chemistry and Pathobiochemistry, University of Mainz, 55099 Mainz, Germany
St George-Hyslop, Peter; Center of Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON M5S 3H2, Canada
Sisodia, Sangram S; Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, IL 60637, United States
De Strooper, Bart; Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology (VIB4), K.U. Leuven, 3000 Leuven, Belgium
HENEKA, Michael ; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Filippov, Mikhail A; Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany
Müller, Ulrike; Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany
van Leuven, Fred; Department of Human Genetics, Experimental Genetics Group, Katholieke Universiteit (K.U.) Leuven, 3000 Leuven, Belgium
Lütjohann, Dieter; Department of Clinical Pharmacology, University of Bonn, 53127 Bonn, Germany
Walter, Jochen; Department of Neurology, University of Bonn, 53127 Bonn, Germany ; Molecular Cell Biology, University of Bonn, 53127 Bonn, Germany
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