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Human Molecular Genetics Advance Access published online on December 22, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi041
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Human Molecular Genetics © Oxford University Press 2004; all rights reserved

Article

Elevated Amyloid ß Protein (Aß42) and Late Onset Alzheimer's Disease are Associated with Single Nucleotide Polymorphisms in the Urokinase-Type Plasminogen Activator Gene

Nilüfer Ertekin-Taner 1, James Ronald 1, Lars Feuk 2, Jonathan Prince 2, Michael Tucker 3, Linda Younkin 1, Maria Hella 1, Shushant Jain 1, Alyssa Hackett 1, Leah Scanlin 1, Jason Kelly 1, Muthoni Kihiko-Ehman 3, Matthew Neltner 3, Louis Hersh 4, Mark Kindy 4, William Markesbery 4, Michael Hutton 1, Mariza de Andrade 5, Ronald C. Petersen 6, Neill Graff-Radford 7, Steve Estus 3, Anthony J. Brookes 2, and Steven G. Younkin 1*

1 Mayo Clinic Jacksonville, Department of Neuroscience, 4500 San Pablo Road, Jacksonville, FL 32224
2 Center for Genomics and Bioinformatics, Karolinska Institute, Stockholm, Sweden
3 Department of Physiology, University of Kentucky, Lexington, KY; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY
4 Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY
5 Mayo Clinic Rochester, Department of Health Sciences Research, 200 First Street SW, Rochester, MN, 55905
6 Mayo Clinic Rochester, Department of Neurology, 200 First Street SW, Rochester, MN, 55905
7 Mayo Clinic Jacksonville, Department of Neurology, 4500 San Pablo Road, Jacksonville, FL 32224

* To whom correspondence should be addressed.
Steven G. Younkin, E-mail: younkin.steven{at}mayo.edu


  Abstract

Plasma amyloid ß protein (Aß42) 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 (uPA), which converts plasminogen to plasmin. Aß aggregates induce PLAU expression thereby increasing plasmin, which degrades both aggregated and non-aggregated forms of Aß. We evaluated single nucleotide polymorphisms in PLAU for association with Aß42 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 A{beta}42 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 OR 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 Aß42 in 24 extended LOAD families (p = 0.0006). In knockout mice lacking the PLAU gene, plasma-but not brain-Aß42 as well as A{beta}40 were significantly elevated, also in an age-dependent manner. The PLAU_1 associations were independent of the associations we found between plasma Aß42, 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 Aß42, but additional biological experiments are required to show this definitively.


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