TY - JOUR
T1 - Elevated amyloid β protein (Aβ42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene
AU - Ertekin-Taner, Nilüfer
AU - Roland, James
AU - Feuk, Lars
AU - Prince, Jonathan
AU - Tucker, Michael
AU - Younkin, Linda
AU - Hella, Maria
AU - Jain, Shushant
AU - Hackett, Alyssa
AU - Scanlin, Leah
AU - Kelly, Jason
AU - Kihiko-Ehman, Muthoni
AU - Neltner, Matthew
AU - Hersch, Louis
AU - Kindy, Mark
AU - Markesbery, William
AU - Hutton, Michael
AU - de Andrade, Mariza
AU - Petersen, Ronald C.
AU - Graff-Radford, Neill
AU - Estus, Steve
AU - Brookes, Anthony J.
AU - Younkin, Steven G.
N1 - Funding Information:
We acknowledge the Mayo Clinic and UKy ADRC members for their help in the collection of samples. We are grateful to all of the individuals who participated in this study, without whom this work would not be possible. This study was supported by the NIH grants AG18023 (S.G.Y.), AG06656 (S.G.Y.), AG20903 (N.E.T.), AG21545 (S.E.), 2P50AG05144 (W.M.), a grant from American Federation for Aging Research Grant PD01062 (N.E.T.) and a Robert and Clarice Smith Fellowship (N.E.T.).
PY - 2005/2/1
Y1 - 2005/2/1
N2 - Plasma amyloid β protein (Aβ42) 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. Aβ aggregates induce PLAU expression thereby increasing plasmin, which degrades both aggregated and non-aggregated forms of Aβ. We evaluated single nucleotide polymorphisms (SNPs) in PLAU for association with Aβ42 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 Aβ42 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 Aβ42 in 24 extended LOAD families (P = 0.0006). In knockout mice lacking the PLAU gene, plasma - but not brain - Aβ42 as well as Aβ40 was significantly elevated, also in an age-dependent manner. The PLAU_1 associations were independent of the associations we found among plasma Aβ42, 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 Aβ42, but additional biological experiments are required to show this definitively.
AB - Plasma amyloid β protein (Aβ42) 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. Aβ aggregates induce PLAU expression thereby increasing plasmin, which degrades both aggregated and non-aggregated forms of Aβ. We evaluated single nucleotide polymorphisms (SNPs) in PLAU for association with Aβ42 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 Aβ42 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 Aβ42 in 24 extended LOAD families (P = 0.0006). In knockout mice lacking the PLAU gene, plasma - but not brain - Aβ42 as well as Aβ40 was significantly elevated, also in an age-dependent manner. The PLAU_1 associations were independent of the associations we found among plasma Aβ42, 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 Aβ42, but additional biological experiments are required to show this definitively.
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U2 - 10.1093/hmg/ddi041
DO - 10.1093/hmg/ddi041
M3 - Article
C2 - 15615772
AN - SCOPUS:13544273507
SN - 0964-6906
VL - 14
SP - 447
EP - 460
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 3
ER -