A Functional Polymorphism within Plasminogen Activator Urokinase (PLAU) is Associated with Alzheimer's Disease

Authors

• Matthias Riemenschneider, Technical University of Munich
• Lidija Konta, Technical University of Munich
• Patricia Friedrich, Technical University of Munich
• Sandra Schwarz, Technical University of Munich
• Kevin Taddei, Edith Cowan UniversityFollow
• Frauke Neff, Institute of Pathology
• Alessandro Padovani, Universita` degli Studi di Brescia
• Heike Kolsch, Friedrich Wilhelms Universitat
• Simon Laws, Edith Cowan UniversityFollow
• Norman Klopp, Institute of Epidemiology, Germany
• Heike Bickeboller, University of Gottingen
• Stefan Wagenpfeil, Department of Medical Statistics and Epidemiology
• Jakob Mueller, Technical University of Munich
• Albert Rosenberger, University of Gottingen
• Janine Diehl-Schmid, Technische Universitat Munchen
• Silvana Archetti, Universita degli Studi di Brescia
• Nicola Lautenschlager, University of Western Australia
• Barbara Borroni, Universita degli Studi di Brescia
• Ulrich Muller, University of Giessen
• Thomas Illig, Institute of Epidemiology
• Reinhard Heun, Technical University of Munich
• Rupert Egensperger, University Hospital Muenster
• Jurgen Schlege, Institute of Pathology
• Hans Forstl, Technische Universitat Munchen
• Ralph N. Martins, Edith Cowan University
• German Sib-Pair Study Group, Technical University of Munich
• Alexander Kurz, Technical University of Munich

Document Type

Journal Article

Keywords

Alzheimer's Disease, Plasminogen Activator Urokinase (PLAU), Polymorphism

Publisher

Oxford University Press

Faculty

Faculty of Health and Science

School

School of Computing, Health and Science

RAS ID

4634

Comments

Riemenschneider, M., Konta, L., Friedrich, P., Schwarz, S., Taddei, K. , Neff, F., Padovani, A., Kolsch, H., Laws, S. , Klopp, N., Bickeboller, H., Wagenpfeil, S., Mueller, J., Rosenberger, A., Diehl-Schmid, J., Archetti, S., Lautenschlager, N., Borroni, B., Muller, U., Illig, T., Heun, R., Egensperger, R., Schlegel, J., Forstl, H., Martins, R. N., & Kurz, A. (2006). A functional polymorphism within Plasminogen Activator Urokinase (PLAU) is associated with Alzheimer's disease. Human Molecular Genetics, 15(16), 2446-2456. Available here

Abstract

A number of susceptibility loci for Alzheimer's disease (AD) have been identified including a region on Chromosome 10q21–q22. 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

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