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

• Published in: Human molecular genetics 2006-08, Vol.15 (16), p.2446-2456
• Main Authors: Riemenschneider, Matthias, Konta, Lidija, Friedrich, Patricia, Schwarz, Sandra, Taddei, Kevin, Neff, Frauke, Padovani, Alessandro, Kölsch, Heike, Laws, Simon M., Klopp, Norman, Bickeböller, Heike, Wagenpfeil, Stefan, Mueller, Jakob C., Rosenberger, Albert, Diehl-Schmid, Janine, Archetti, Silvana, Lautenschlager, Nicola, Borroni, Barbara, Müller, Ulrich, Illig, Thomas, Heun, Reinhard, Egensperger, Rupert, Schlegel, Jürgen, Förstl, Hans, Martins, Ralph N., Kurz, Alexander
• Format: Article
• Language: English
• Subjects: Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease - genetics; Apolipoproteins E - genetics; Biological and medical sciences; Brain - ultrastructure; Case-Control Studies; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Diagnosis; Female; Fundamental and applied biological sciences. Psychology; Gene Frequency; Genetic Linkage; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Humans; Linkage Disequilibrium; Male; Medical sciences; Middle Aged; Molecular and cellular biology; Neurology; Plaque, Amyloid - ultrastructure; Polymorphism, Genetic; Reproducibility of Results; Sequence Analysis, DNA; Urokinase-Type Plasminogen Activator - genetics
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddl167

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.