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Human Molecular Genetics, 2000, Vol. 9, No. 2 303-310
© 2000 Oxford University Press

Alzheimer’s presenilin 1 is a putative membrane receptor for rab GDP dissociation inhibitor

W. Scheper+, R. Zwart, P. van der Sluijs1, W. Annaert2, W.A. van Gool and F. Baas§

Laboratory Neurozintuigen and Department of Neurology, Academic Medical Center, PO Box 22700, 1105 AZ Amsterdam, The Netherlands, 1Department of Cell Biology, Utrecht University School of Medicine, 3584 KX Utrecht, The Netherlands and 2Neuronal Cell Biology and Gene Transfer Laboratory, Flanders Interuniversitary Institute for Biotechnology, Center for Human Genetics, KULeuven, B-3000 Leuven, Belgium

Mutations in the presenilin 1 (PS-1) gene cause Alzheimer’s disease (AD). These mutations alter the processing of the amyloid precursor protein (APP) by increasing the production of the fibrillogenic amyloid fragment, Aß1–42/43. Since the secretase activities that process APP are localized in different intracellular compartments, it is likely that membrane transport is a key factor in the pathogenesis of AD. In this report we provide evidence for a direct connection between PS-1 and membrane transport. We show that the N-terminus of PS-1 binds to rab GDP dissociation inhibitor (rabGDI), a regulatory factor in vesicle transport. In PS-1-deficient neurons we found a 2-fold decrease in the amount of rabGDI associated with membranes. Our findings are compatible with PS-1 being a membrane receptor for rabGDI. This is in line with a role of PS-1 in the regulation of protein trafficking in the ER/Golgi, which can modulate the production of Aß.

+ Present address: University of Cambridge, Cambridge Institute for Medical Research, Hills Road, Cambridge CB2 2XY, UK

§ To whom correspondence should be addressed. Tel: +31 20 5665998; Fax: +31 20 5664440; Email: f.baas@amc.uva.nl


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