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Gerd Multhaup
Ligand associated conformational changes of the amyloid precursor protein APP
Current Research
APP is suggested to be involved in maintaining the Cu-homeostasis within the CNS, together with the prion protein (PrP) that also binds copper very specifically. Apart from their action to monomerize APP dimers, copper ions facilitate the non-amyloidogenic cleavage and attenuate the amyloidogenic cleavage of APP. Thus, we conclude that dimeric forms of APP inside the cell are the preferred targets of the ß-secretase that initiates amyloid formation.
We would like to understand how the homophilic interaction domains and the copper binding site of APP regulate the complex formation between APP and ß-secretase and in which cellular compartments the proteolytic cleavage event can occur which is required for amyloid formation.Projects for a doctoral thesis
How APP mutants (affecting copper binding and/or dimerization) are transported and processed within hippocampal neurons from APP knock-out mice. Our goal is to study the physiological function of APP dimerization and its conformational requirement for APP/ß-secretase interactions.
Contact:
Priv.-Doz. Dr. Gerd Multhaup
ZMBH-Center for Molecular Biology
Im Neuenheimer Feld 282
69120 Heidelberg, Germany
Tel: - 49 - 6221 - 54 68 49
Fax: - 49 - 6221 - 54 58 91
modem: +49-6221-54 68 49
email: g.multhaup@zmbh.uni-heidelberg.de
www.zmbh.uni-heidelberg.de/Multhaup/
Selected Publications
Multhaup, G., Schlicksupp, A., Hesse, L., Beher, D., Ruppert, T., Masters, C. L. and Beyreuther, K. (1996). The amyloid precursor protein of Alzheimer's disease in the reduction of copper(II) to copper(I). Science, 271, 1406-1409.
Multhaup, G., Ruppert, T., Schlicksupp, A., Hesse, L., Bill, E., Pipkorn, R., Masters, C.L. and Beyreuther, K. (1998). APP-copper complexes undergo site-specific fragmentation in the reduction of hydrogen peroxide. Biochemistry, 37, 7224-7230.
Borchardt, T., Camakaris, J., Cappai, R., Masters, C. L., Beyreuther, K., and Multhaup, G. (1999). Copper inhibits ß-amyloid production and stimulates the non-amyloidogenic pathway of amyloid precursor protein (APP) secretion. Biochem J 344, 461-467.
Strausak, D., Mercer, J.F.B., Dieter, H.H., Stremmel, W. and Multhaup, G. (2001). Copper in disorders with neurological symptoms: Alzheimer's disease, Menkes and Wilson disease. Brain Res Bull, in press.
Bodendorf, U., Fischer, F., Bodian, D., Multhaup, G. and Paganetti, P. (2001). A splice variant of ß-secretase deficient in the amyloidogenic processing of the amyloid precursor protein. J Biol Chem, in press.
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