Elevated amyloid β protein (Aβ42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene

Nilufer Taner, James Roland, Lars Feuk, Jonathan Prince, Michael Tucker, Linda Younkin, Maria Hella, Shushant Jain, Alyssa Hackett, Leah Scanlin, Jason Kelly, Muthoni Kihiko-Ehman, Matthew Neltner, Louis Hersch, Mark Kindy, William Markesbery, Michael Hutton, Mariza De Andrade, Ronald Carl Petersen, Neill R Graff RadfordSteve Estus, Anthony J. Brookes, Steven G Younkin

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)447-460
Number of pages14
JournalHuman Molecular Genetics
Volume14
Issue number3
DOIs
StatePublished - Feb 1 2005

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Amyloidogenic Proteins
Urokinase-Type Plasminogen Activator
Single Nucleotide Polymorphism
Alzheimer Disease
Genes
Fibrinolysin
Genotype
Haplotypes
Plasminogen
Proline
Knockout Mice
Leucine
Blood Proteins
Exons
Chromosomes
Odds Ratio
Mutation
Brain

ASJC Scopus subject areas

  • Genetics

Cite this

Elevated amyloid β protein (Aβ42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene. / Taner, Nilufer; Roland, James; Feuk, Lars; Prince, Jonathan; Tucker, Michael; Younkin, Linda; Hella, Maria; Jain, Shushant; Hackett, Alyssa; Scanlin, Leah; Kelly, Jason; Kihiko-Ehman, Muthoni; Neltner, Matthew; Hersch, Louis; Kindy, Mark; Markesbery, William; Hutton, Michael; De Andrade, Mariza; Petersen, Ronald Carl; Graff Radford, Neill R; Estus, Steve; Brookes, Anthony J.; Younkin, Steven G.

In: Human Molecular Genetics, Vol. 14, No. 3, 01.02.2005, p. 447-460.

Research output: Contribution to journalArticle

Taner, N, Roland, J, Feuk, L, Prince, J, Tucker, M, Younkin, L, Hella, M, Jain, S, Hackett, A, Scanlin, L, Kelly, J, Kihiko-Ehman, M, Neltner, M, Hersch, L, Kindy, M, Markesbery, W, Hutton, M, De Andrade, M, Petersen, RC, Graff Radford, NR, Estus, S, Brookes, AJ & Younkin, SG 2005, 'Elevated amyloid β protein (Aβ42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene', Human Molecular Genetics, vol. 14, no. 3, pp. 447-460. https://doi.org/10.1093/hmg/ddi041
Taner, Nilufer ; Roland, James ; Feuk, Lars ; Prince, Jonathan ; Tucker, Michael ; Younkin, Linda ; Hella, Maria ; Jain, Shushant ; Hackett, Alyssa ; Scanlin, Leah ; Kelly, Jason ; Kihiko-Ehman, Muthoni ; Neltner, Matthew ; Hersch, Louis ; Kindy, Mark ; Markesbery, William ; Hutton, Michael ; De Andrade, Mariza ; Petersen, Ronald Carl ; Graff Radford, Neill R ; Estus, Steve ; Brookes, Anthony J. ; Younkin, Steven G. / Elevated amyloid β protein (Aβ42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene. In: Human Molecular Genetics. 2005 ; Vol. 14, No. 3. pp. 447-460.
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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 Carl

AU - Graff Radford, Neill R

AU - Estus, Steve

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AU - Younkin, Steven G

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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.

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