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Experimental Genetics Group

Bolleke Abstract   Pijltje
Loss of gamma-secretase function impairs endocytosis of lipoprotein particles and membrane cholesterol homeostasis.

J Neurosci. 2008 Nov 12;28(46):12097-106.

Tamboli IY1, Prager K1, Thal DR3, Thelen KM2, Dewachter I4, Pietrzik CU5, St George-Hyslop P6, Sisodia SS7, De Strooper B8, Heneka MT1, Filippov MA9, Müller U9, van Leuven F4, Lütjohann D2, Walter J1.

1Department of Neurology, University of Bonn, Bonn, Germany.
2Department of Clinical Pharmacology, University of Bonn, Bonn, Germany.
3Institute of Pathology, University of Ulm, Ulm, Germany.
4Department of Human Genetics, Experimental Genetics Group, Katholieke Universiteit (K.U.) Leuven, Leuven, Belgium.
5Department of Physiological Chemistry and Pathobiochemistry, University of Mainz, Mainz, Germany.
6Center of Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
7Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois.
8Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology (VIB) and K.U.Leuven, Leuven, Belgium.
9Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany.

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.

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