Since 2006

Director of the NAR

1987-2007
Professor at the ZMBH
1978-87


Professor at the Institute for Genetics, University of Cologne, Germany
1970-80

Postdoctoral work at Inst. for Genetics, Univ. of Cologne, Germany

1969-70



Training in Mol. Biol. at Lab for Mol. Biol., MRC, Cambridge, GB and at Biol. Labs., Harvard Univ., Cambridge, Mass. USA
1968

Dr.rer.nat., MPI for Biochem., Munich, Germany


Contact:
Netzwerk Alternsforschung (NAR), Bergheimer Str. 20
69115 Heidelberg, Germany
Tel.: + 49-6221 54 6845
Fax.: +49-6221 54 8100

beyreuther@nar.uni-hd.de

Link to Netzwerk AlternsfoRschung:
http://www.nar.uni-heidelberg.de

Konrad Beyreuther´s Laboratory


Molecular & cellular biology of Alzheimer's disease and related disorders

We have a long-standing interest in the genetics, molecular and cellular biology of neurodegenerative disorders. Our aim is to unravel the physiological and pathogenetic function of key genes and mechanisms which underly and drive the processes causing dementia. For this we use Alzheimer's disease (AD) as a model. This disease is the most common human neurodegenerative disorder afflicting 1,4 percent of the population in the Western world. Its most characteristic molecular and cellular hallmarks are the accumulations of intraneuronal Aβ peptides and extracellular deposits of this Aβ peptide (Fig. 1) which are the cause of synaptic dysfunction and neuronal loss. Aβ is a 40-43 amino acid fragment, formed from neuronal amyloid precursor protein (APP) by two sequential proteolytic cleavage events. The first cleavage takes place within the ectodomain of APP and is mediated by β-secretase (BACE). The second cleavage generates the C-terminus of Aβ and occurs within the transmembrane domain of APP by three consecutive cleavages termed ε-, ζ- and γ-cleavage which are all mediated by the γ-secretase complex. In order to understand better the mechanism of this second cleavage within the lipid bilayer, we initiated experiments designed to unravel the mechanism of this process by expressing APP molecules carrying mutations altering the length of its transmembrane domain or allowing to introduce charged groups into it. Together with Stefan Lichtenthaler, Beate Grziwa, and Tobias Hartmann in our lab, this approach led to the first experimental demonstration that the site at which γ-secretase cleaves is the middle of the lipid bilayer.

Selected Publications

Tienari et al. (1996). Neuronal sorting and processing of amyloid precursor protein: Implications to Alzheimer disease. Cold Spring Harbor Quant. Symp. 61: 575-585.

Weidemann et al. (1997). Formation of stable complexes between two Alzheimer-disease gene products: presenilin-2 and β-amyloid precursor protein. Nature Med. 3:328-332.

Lichtenthaler et al. (1999). Mechanism of the cleavage specificity of Alzheimer disease γ-secretase revealed by phenylalanine-scanning mutagenesis of the transmembrane domain of APP. Proc Natl Acad Sci USA 96: 3053-3058.

Fassbender et al. (2001). Simvastatin strongly reduces Alzheimer disease Aβ42 and Aβ40 levels in vitro and in vivo . Proc Natl Acad Sci USA 98 : 5856-5861.

Kins et al. (2001). Reduced PP2A activity induces hyperphosphorylation and altered compartmentalization of tau in transgenic mice. J Biol Chem: 276, 38193-38200.

Lichtenthaler et al. (2002) The intramembrane cleavage site of the amyloid precursor protein depends on the length of its transmembrane domain. Proc Natl Acad Sci USA 99: 1365-1370.

Kins et al. (2003). Hyperphosphorylation and somatodendritic localization of tau in PP2A dominant negative mutant mice is associated with activation of ERK and JNK signaling. J. Am. Path., 2003, 163 (3), 833-843.

Eggert (2004). The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves α -, β -, γ -, and ε -like cleavages. Modulation of APLP-1 processing by N-glycosylation. J Biol Chem 279: 18146-18156.


Lab

K. Beyreuther H. Bujard B. Bukau C. Clayton B. Dobberstein S. Erhardt O. Gruss M. Lemberg
M. Mayer  F. Melchior  H. Schaller E. Schiebel M. Seedorf V. Sourjik G. Stoecklin