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Human Molecular Genetics Advance Access originally published online on July 6, 2006
Human Molecular Genetics 2006 15(16):2446-2456; doi:10.1093/hmg/ddl167
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Matthias Riemenschneider1,*, Lidija Konta1, Patricia Friedrich1, Sandra Schwarz1, Kevin Taddei5,13, Frauke Neff2, Alessandro Padovani6, Heike Kölsch7, Simon M. Laws1,13, Norman Klopp8, Heike Bickeböller9, Stefan Wagenpfeil3, Jakob C. Mueller1,3,14, Albert Rosenberger9, Janine Diehl-Schmid4, Silvana Archetti6, Nicola Lautenschlager10, Barbara Borroni6, Ulrich Müller11, Thomas Illig8, Reinhard Heun7, Rupert Egensperger12, Jürgen Schlegel2, Hans Förstl4, Ralph N. Martins5,13 the German Sib-Pair Study Group, Alexander Kurz4

1 Neurochemistry and Neurogenetics Laboratory, Department of Psychiatry and Psychotherapy, 2 Institute of Pathology, 3 Department of Medical Statistics and Epidemiology, 4 Department of Psychiatry and Psychotherapy, Technische Universität München (TUM), Ismaningerstr. 22, 81675 Munich, Germany, 5 Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Perth, Western Australia, 6 Clinica Neurologica, Università degli Studi di Brescia, Brescia, Italy, 7 Department of Psychiatry and Psychotherapy, Friedrich Wilhelms Universität, Bonn, Germany, 8 Institute of Epidemiology, GSF, München-Neuherberg, Germany, 9 Department of Genetic Epidemiology, University of Göttingen, Germany, 10 School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia, 11 Institute of Human Genetics, University of Giessen, Germany, 12 Institute of Neuropathology, University Hospital Muenster, Germany, 13 Alzheimer's and Aging, School of Biomedical and Sports Science, Edith Cowan University, Joondalup, Australia and 14 Hertie-Institute for Clinical Brain Research, Tuebingen, Germany

* To whom correspondence should be addressed: Tel: +49 8941404214; Fax: +49 8941404888; Email: m.riemenschneider{at}lrz.tu-muenchen.de

Received March 22, 2006; Accepted July 1, 2006

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 (Aß) 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 Aß proteins.


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