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Riemenschneider, M.* ; Konta, L.* ; Friedrich, P.* ; Schwarz, S.* ; Taddei, K.* ; Neff, F.* ; Padovani, A.* ; Kölsch, H.* ; Laws, S.M.* ; Klopp, N. ; Bickeböller, H.* ; Wagenpfeil, S.* ; Mueller, J.C.* ; Rosenberger, A.* ; Diehl-Schmid, J.* ; Archetti, S.* ; Lautenschlager, N.* ; Borroni, B.* ; Müller, U.* ; Illig, T. ; Heun, R.* ; Egensperger, R.* ; Schlegel, J.* ; Förstl, H.* ; Martins, R.N.* ; Kurz, A.*

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

Hum. Mol. Genet. 15, 2446-2456 (2006)
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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 beta) 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 A beta proteins.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Quellenangaben Volume: 15, Issue: 16, Pages: 2446-2456 Article Number: , Supplement: ,
Publisher Oxford University Press
Reviewing status Peer reviewed