A functional polymorphism within plasminogen activator urokinase (PLAU) is associated with Alzheimer's disease

Matthias Riemenschneider*, Lidija Konta, Patricia Friedrich, Sandra Schwarz, Kevin Taddei, Frauke Neff, Alessandro Padovani, Heike Kölsch, Simon M. Laws, Norman Klopp, Heike Bickeböller, Stefan Wagenpfeil, Jakob C. Mueller, Albert Rosenberger, Janine Diehl-Schmid, Silvana Archetti, Nicola Lautenschlager, Barbara Borroni, Ulrich Müller, Thomas Illig & 39 others Reinhard Heun, Rupert Egensperger, Jürgen Schlegel, Hans Förstl, Ralph N. Martins, Alexander Kurz, M. Krömmer, B. Cramer, A. Klimbacher, P. Belcredi, G. Laux, Eberl, H. E. Klein, Bernd Ibach, Eberhard Koenig, Barbara Romero, Manfred Wolfersdorf, Michael Schüler, Mathias Berger, Schmidtke, E. Jost, M. Schmauss, Ch Steber, R. Heinrich, Wiegele Britta, H. P. Volz, M. Jähnel, M. Dose, Macquard, Bremer, N. Braunisch, H. Nickl, L. Blaha, S. Herpich, H. W. Dietl, R. Schüttler, R. Hess, M. Philipp, A. Wermuth

*Corresponding author for this work

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

A number of susceptibility loci for Alzheimer's disease (AD) have been identified including a region on Chromosome 10q21-22. Within this region the plasminogen activator urokinase gene (PLAU) was considered as a reasonable candidate from its functional implication in plasmin generation, a serine protease capable of degrading beta-Amyloid (Aβ) protein. We screened 56 single nucleotide polymorphisms (SNPs) around PLAU using 1751 individuals from four independent case-control samples (Munich, N = 679; Bonn N = 282; Brescia (Italy) N = 219; Perth (Australia) N = 557 and one discordant sib-pair sample (Munich N = 622). In brain tissue samples of neuropathologically confirmed cases with AD (N = 33) we analyzed plaque counts according to the risk allele. We identified that one functional exonic SNP (rs2227564) is associated with development of AD using the four independent case-control samples (Munich, P = 0.02; Bonn, P = 0.005; Brescia (Italy), P = 0.001; Perth (Australia), P = 0.03) and the discordant sib-pair sample (P = 0.001). In brain tissue, from neuropathologically confirmed cases with AD, we identified significantly higher plaque counts in carriers of the risk allele (N = 6; 60.3 ± 16.9) compared with non-carriers (N = 9; 26.3±8.8; P = 0.007). This study provides compelling evidence of a genetic and functional involvement of a common PLAU variant into the pathogenesis of AD. Further functional investigations are warranted to elucidate the specific role of PLAU, respectively, PLAU variants in the metabolism of Aβ proteins.

Original languageEnglish
Pages (from-to)2446-2456
Number of pages11
JournalHuman Molecular Genetics
Volume15
Issue number16
DOIs
Publication statusPublished - 15 Aug 2006
Externally publishedYes

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