Publication
A functional polymorphism within plasminogen activator urokinase (PLAU) is associated with Alzheimer's disease
Publisher:
Oxford University Press (OUP)
Date:
16-06-2006
DOI:
10.1093/HMG/DDL167
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 (Abeta) protein. We screened 56 single nucleotide polymorphisms (SNPs) around PLAU using 1751 in iduals from four independent case-control s les (Munich, N=679 Bonn N=282 Brescia (Italy) N=219 Perth (Australia) N=557 and one discordant sib-pair s le (Munich N=622). In brain tissue s les 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 s les (Munich, P=0.02 Bonn, P=0.005 Brescia (Italy), P=0.001 Perth (Australia), P=0.03) and the discordant sib-pair s le (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 Abeta proteins.