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The Journal of Neuroscience, November 12, 2008, 28(46):12097-12106; doi:10.1523/JNEUROSCI.2635-08.2008

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Neurobiology of Disease
Loss of -Secretase Function Impairs Endocytosis of Lipoprotein Particles and Membrane Cholesterol Homeostasis

Irfan Y. Tamboli,¹ Kai Prager,¹ Dietmar R. Thal,³ Karin M. Thelen,² Ilse Dewachter,⁴ Claus U. Pietrzik,⁵ Peter St. George-Hyslop,⁶ Sangram S. Sisodia,⁷ Bart De Strooper,⁸ Michael T. Heneka,¹ Mikhail A. Filippov,⁹ Ulrike Müller,⁹ Fred van Leuven,⁴ Dieter Lütjohann,² and Jochen Walter¹

Departments of ¹Neurology and ²Clinical Pharmacology, University of Bonn, 53127 Bonn, Germany, ³Institute of Pathology, University of Ulm, 89081 Ulm, Germany, ⁴Department of Human Genetics, Experimental Genetics Group, Katholieke Universiteit (K.U.) Leuven, 3000 Leuven, Belgium, ⁵Department of Physiological Chemistry and Pathobiochemistry, University of Mainz, 55099 Mainz, Germany, ⁶Center of Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada M5S 3H2, ⁷Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois 60637, ⁸Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology (VIB4) and K.U. Leuven, 3000 Leuven, Belgium, and ⁹Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany

Correspondence should be addressed to Dr. Jochen Walter, Molecular Cell Biology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany. Email: jochen.walter{at}ukb.uni-bonn.de

Presenilins (PSs) are components of the -secretase complex that mediates intramembranous cleavage of type I membrane proteins. We show that -secretase is involved in the regulation of cellular lipoprotein uptake. Loss of -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 -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.

Key words: presenilin; lipoprotein uptake; apo E; SREBP2; cholesterol; APP

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Received June 10, 2008; revised Sept. 1, 2008; accepted Sept. 23, 2008.

Correspondence should be addressed to Dr. Jochen Walter, Molecular Cell Biology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany. Email: jochen.walter{at}ukb.uni-bonn.de

This article has been cited by other articles:

				D. Waschbusch, S. Born, V. Niediek, N. Kirchgessner, I. Y. Tamboli, J. Walter, R. Merkel, and B. Hoffmann Presenilin 1 Affects Focal Adhesion Site Formation and Cell Force Generation via c-Src Transcriptional and Posttranslational Regulation J. Biol. Chem., April 10, 2009; 284(15): 10138 - 10149. [Abstract] [Full Text] [PDF]

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