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

Markus J. Riemenschneider | Zendy; Lidija Konta | Zendy; Patricia F. Friedrich | Zendy; Sandra Schwarz | Zendy; Kevin Taddei | Zendy; Frauke Neff | Zendy; Alessandro Padovani | Zendy; Heike Kölsch | Zendy; Simon M. Laws | Zendy; Norman Klopp | Zendy; Heike Bickeböller | Zendy; Stefan Wagenpfeil | Zendy; Jakob C. Mueller | Zendy; Albert Rosenberger | Zendy; Janine DiehlSchmid | Zendy; Silvana Archetti | Zendy; Nicola T. Lautenschlager | Zendy; Barbara Borroni | Zendy; Ulrich Müller | Zendy; Thomas Illig | Zendy; Reinhard Heun | Zendy; Rupert Egensperger | Zendy; Jürgen Schlegel | Zendy; Hans Förstl | Zendy; Ralph N. Martins | Zendy; Alexander Kurz | Zendy

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

Author(s) -

Markus J. Riemenschneider,

Lidija Konta,

Patricia F. Friedrich,

Sandra Schwarz,

Kevin Taddei,

Frauke Neff,

Alessandro Padovani,

Heike Kölsch,

Simon M. Laws,

Norman Klopp,

Heike Bickeböller,

Stefan Wagenpfeil,

Jakob C. Mueller,

Albert Rosenberger,

Janine DiehlSchmid,

Silvana Archetti,

Nicola T. Lautenschlager,

Barbara Borroni,

Ulrich Müller,

Thomas Illig,

Reinhard Heun,

Rupert Egensperger,

Jürgen Schlegel,

Hans Förstl,

Ralph N. Martins,

Alexander Kurz

Publication year - 2006

Publication title -

human molecular genetics

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.811

H-Index - 276

eISSN - 1460-2083

pISSN - 0964-6906

DOI - 10.1093/hmg/ddl167

Subject(s) - biology , single nucleotide polymorphism , plasminogen activator , allele , alzheimer's disease , genetics , urokinase , pathogenesis , snp , plasmin , microbiology and biotechnology , gene , pathology , disease , genotype , immunology , medicine , biochemistry , enzyme

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.

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