title: Elevated amyloid beta protein (Abeta42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene.
abstract: Plasma amyloid beta protein (Abeta42) levels and late onset Alzheimer's disease (LOAD) have been linked to the same region on chromosome 10q. The PLAU gene within this region encodes urokinase-type plasminogen activator, which converts plasminogen to plasmin. Abeta aggregates induce PLAU expression thereby increasing plasmin, which degrades both aggregated and non-aggregated forms of Abeta. We evaluated single nucleotide polymorphisms (SNPs) in PLAU for association with Abeta42 and LOAD. PLAU SNP compound genotypes composed of haplotype pairs showed significant association with AD in three independent case-control series. PLAU SNP haplotypes associated significantly with plasma Abeta42 in 10 extended LOAD families. One of the SNPs analyzed was a missense C/T polymorphism in exon 6 of PLAU (PLAU_1=rs2227564), which causes a proline to leucine change (P141L). We analyzed PLAU_1 for association with AD in six case-control series and 24 extended LOAD families. The CT and TT PLAU_1 genotypes showed association (P=0.05) with an overall estimated odds ratio of 1.2 (1.0-1.5). The CT and TT genotypes of PLAU_1 were also associated with significant age-dependent elevation of plasma Abeta42 in 24 extended LOAD families (P=0.0006). In knockout mice lacking the PLAU gene, plasma--but not brain--Abeta42 as well as Abeta40 was significantly elevated, also in an age-dependent manner. The PLAU_1 associations were independent of the associations we found among plasma Abeta42, LOAD and variants in the IDE or VR22 region. These results provide strong evidence that PLAU or a nearby gene is involved in the development of LOAD. PLAU_1 is a plausible pathogenic mutation that could act by increasing Abeta42, but additional biological experiments are required to show this definitively.
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Nilüfer
authors.initials: N
authors.lastname: Ertekin-Taner
authors.forename: James
authors.initials: J
authors.lastname: Ronald
authors.forename: Lars
authors.initials: L
authors.lastname: Feuk
authors.forename: Jonathan
authors.initials: J
authors.lastname: Prince
authors.forename: Michael
authors.initials: M
authors.lastname: Tucker
authors.forename: Linda
authors.initials: L
authors.lastname: Younkin
authors.forename: Maria
authors.initials: M
authors.lastname: Hella
authors.forename: Shushant
authors.initials: S
authors.lastname: Jain
authors.forename: Alyssa
authors.initials: A
authors.lastname: Hackett
authors.forename: Leah
authors.initials: L
authors.lastname: Scanlin
authors.forename: Jason
authors.initials: J
authors.lastname: Kelly
authors.forename: Muthoni
authors.initials: M
authors.lastname: Kihiko-Ehman
authors.forename: Matthew
authors.initials: M
authors.lastname: Neltner
authors.forename: Louis
authors.initials: L
authors.lastname: Hersh
authors.forename: Mark
authors.initials: M
authors.lastname: Kindy
authors.forename: William
authors.initials: W
authors.lastname: Markesbery
authors.forename: Michael
authors.initials: M
authors.lastname: Hutton
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Neill
authors.initials: N
authors.lastname: Graff-Radford
authors.forename: Steve
authors.initials: S
authors.lastname: Estus
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Brookes
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010375:Pedigree; D010446:Peptide Fragments / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D014568:Urokinase-Type Plasminogen Activator