Human Molecular Genetics Advance Access published online on July 6, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl167
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1 Neurochemistry and Neurogenetics Laboratory, Department of Psychiatry and Psycho-therapy, Technische Universität München (TUM), Ismaningerstr. 22, 81675 Munich, Germany
* To whom correspondence should be addressed. 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 (A 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 to 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 A
Received March 22, 2006
Revised July 1, 2006
Accepted July 1, 2006
Article
A functional polymorphism within plasminogen activator urokinase (PLAU) is associated with Alzheimer's disease
Matthias Riemenschneider 1 *,
Lidija Konta 2,
Patricia Friedrich 2,
Sandra Schwarz 2,
Kevin Taddei 3,
Frauke Neff 4,
Alessandro Padovani 5,
Heike Kölsch 6,
Simon M Laws 7,
Norman Klopp 8,
Heike Bickeböller 9,
Stefan Wagenpfeil 10,
Jakob C. Mueller 11,
Albert Rosenberger 9,
Janine Diehl-Schmid 12,
Silvana Archetti 5,
Nicola Lautenschlager 13,
Barbara Borroni 5,
Ulrich Müller 14,
Thomas Illig 8,
Reinhard Heun 6,
Rupert Egensperger 15,
Jürgen Schlegel 4,
Hans Förstl 12,
and
Ralph N Martins 3,
German sib-pair study group,
and
Alexander Kurz 12
2 Neurochemistry and Neurogenetics Laboratory, Department of Psychiatry and Psycho-therapy, Technische Universität München (TUM), Germany
3 Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Perth, Western Australia; Alzheimer's and Aging, School of Biomedical and Sports Science, Edith Cowan University, Joondalup, Australia
4 Institute of Pathology, TUM, Germany
5 Clinica Neurologica, Università degli Studi di Brescia, Brescia, Italy
6 Department of Psychiatry and Psychotherapy, Friedrich Wilhelms Universität, Bonn, Germany
7 Neurochemistry and Neurogenetics Laboratory, Department of Psychiatry and Psycho-therapy, Technische Universität München (TUM), Germany; Alzheimer's and Aging, School of Biomedical and Sports Science, Edith Cowan University, Joondalup, Australia
8 Institute of Epidemiology, GSF, München-Neuherberg, Germany
9 Department of Genetic Epidemiology, University of Göttingen, Germany
10 Department of Medical Statistics and Epidemiology, TUM, Germany
11 Neurochemistry and Neurogenetics Laboratory, Department of Psychiatry and Psycho-therapy, Technische Universität München (TUM), Germany; Department of Medical Statistics and Epidemiology, TUM, Germany; Hertie-Institute for Clinical Brain Research, Tuebingen, Germany
12 Department of Psychiatry and Psychotherapy, TUM, Germany
13 School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia
14 Institute of Human Genetics, University of Giessen, Germany
15 Institute of Neuropathology, University Hospital Muenster, Germany
Matthias Riemenschneider, E-mail: m.riemenschneider{at}lrz.tu-muenchen.de
Abstract 
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