title: A functional polymorphism within plasminogen activator urokinase (PLAU) is associated with Alzheimer's disease.
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 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 Abeta proteins.
authors.affiliation: Neurochemistry and Neurogenetics Laboratory, Department of Psychiatry and Psychotherapy, Technische Universitat München, Ismaningerstrasse 22, 81675 Munich, Germany. m.riemenschneider@lrz.tu-muenchen.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Riemenschneider
authors.forename: Lidija
authors.initials: L
authors.lastname: Konta
authors.forename: Patricia
authors.initials: P
authors.lastname: Friedrich
authors.forename: Sandra
authors.initials: S
authors.lastname: Schwarz
authors.forename: Kevin
authors.initials: K
authors.lastname: Taddei
authors.forename: Frauke
authors.initials: F
authors.lastname: Neff
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padovani
authors.forename: Heike
authors.initials: H
authors.lastname: Kölsch
authors.forename: Simon M
authors.initials: SM
authors.lastname: Laws
authors.forename: Norman
authors.initials: N
authors.lastname: Klopp
authors.forename: Heike
authors.initials: H
authors.lastname: Bickeböller
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagenpfeil
authors.forename: Jakob C
authors.initials: JC
authors.lastname: Mueller
authors.forename: Albert
authors.initials: A
authors.lastname: Rosenberger
authors.forename: Janine
authors.initials: J
authors.lastname: Diehl-Schmid
authors.forename: Silvana
authors.initials: S
authors.lastname: Archetti
authors.forename: Nicola
authors.initials: N
authors.lastname: Lautenschlager
authors.forename: Barbara
authors.initials: B
authors.lastname: Borroni
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Reinhard
authors.initials: R
authors.lastname: Heun
authors.forename: Rupert
authors.initials: R
authors.lastname: Egensperger
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schlegel
authors.forename: Hans
authors.initials: H
authors.lastname: Förstl
authors.forename: Ralph N
authors.initials: RN
authors.lastname: Martins
authors.forename: Alexander
authors.initials: A
authors.lastname: Kurz
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000648:ultrastructure; D016022:Case-Control Studies; D003933:Diagnosis; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D058225:Plaque, Amyloid / Q000648:ultrastructure; D011110:Polymorphism, Genetic; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics*
chemical_list: D001057:Apolipoproteins E; D014568:Urokinase-Type Plasminogen Activator