Skip to main content

Advertisement

SpringerLink
Log in

Association of late-onset Alzheimer disease with a genotype of PLAU, the gene encoding urokinase-type plasminogen activator on chromosome 10q22.2

  • Original Article
  • Published:
Neurogenetics Aims and scope Submit manuscript

Abstract

Urokinase-type plasminogen activator (uPA) converts plasminogen to plasmin. Plasmin is involved in processing of amyloid precursor protein and degrades secreted and aggregated amyloid-β, a hallmark of Alzheimer disease (AD). PLAU, the gene encoding uPA, maps to chromosome 10q22.2 between two regions showing linkage to late-onset AD (LOAD). We genotyped a frequent C/T single nucleotide polymorphism in codon 141 of PLAU (P141L) in 347 patients with LOAD and 291 control subjects. LOAD was associated with homozygous C/C PLAU genotype in the whole sample (χ2=15.7, P=0.00039, df 2), as well as in all sub-samples stratified by gender or APOE ε4 carrier status (χ2≥ 6.84, P≤0.033, df 2). Odds ratio for LOAD due to homozygosity C/C was 1.89 (95% confidence interval 1.37–2.61). PLAU is a promising new candidate gene for LOAD, with allele C (P141) being a recessive risk allele or allele T (L141) conferring protection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.

Similar content being viewed by others

References

  1. Evans DA, Beckett LA, Field TS, Feng L, Albert MS, Bennett DA, Tycko B, Mayeux R (1997) Apolipoprotein E epsilon4 and incidence of Alzheimer disease in a community population of older persons. JAMA 277:822–824

    Google Scholar 

  2. Slooter AJ, Cruts M, Kalmijn S, Hofman A, Breteler MM, Van Broeckhoven C, Duijn CM van (1998) Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study. Arch Neurol 55:964–968

    Google Scholar 

  3. Tol J, Slooter AJC, Duijn CM van (1999) Genetic factors in early- and late-onset Alzheimer's disease. In: Mayeux R, Christen Y (eds) Epidemiology of Alzheimer's disease: from gene to prevention. Springer, Berlin Heidelberg New York, pp 33–39

  4. Warwick Daw E, Payami H, Nemens EJ, Nochlin D, Bird TD, Schellenberg GD, Wijsman EM (2000) The number of trait loci in late-onset Alzheimer disease. Am J Hum Genet 66:196–204

    Google Scholar 

  5. Rao VS, Cupples A, Duijn CM van, Kurz A, Green RC, Chui H, Duara R, Auerbach SA, Volicer L, Wells J, Broeckhoven C van, Growdon JH, Haines JL, Farrer LA (1996) Evidence for major gene inheritance of Alzheimer disease in families of patients with and without apolipoprotein E epsilon 4. Am J Hum Genet 59:664–675

    Google Scholar 

  6. Blacker D, Bertram L, Saunders AJ, Moscarillo TJ, Albert MS, Wiener H, Perry RT, Collins JS, Harrell LE, Go RC, Mahoney A, Beaty T, Fallin MD, Avramopoulos D, Chase GA, Folstein MF, McInnis MG, Bassett SS, Doheny KJ, Pugh EW, Tanzi RE (2003) Results of a high-resolution genome screen of 437 Alzheimer's disease families. Hum Mol Genet 12:23–32

    Google Scholar 

  7. Bertram L, Blacker D, Mullin K, Keeney D, Jones J, Basu S, Yhu S, McInnis MG, Go RC, Vekrellis K, Selkoe DJ, Saunders AJ, Tanzi RE (2000) Evidence for genetic linkage of Alzheimer's disease to chromosome 10q. Science 290:2302–2303

    Google Scholar 

  8. Ertekin-Taner N, Graff-Radford N, Younkin LH, Eckman C, Baker M, Adamson J, Ronald J, Blangero J, Hutton M, Younkin SG (2000) Linkage of plasma Abeta42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. Science 290:2303–2304

    Google Scholar 

  9. Myers A, Holmans P, Marshall H, Kwon J, Meyer D, Ramic D, Shears S, Booth J, DeVrieze FW, Crook R, Hamshere M, Abraham R, Tunstall N, Rice F, Carty S, Lillystone S, Kehoe P, Rudrasingham V, Jones L, Lovestone S, Perez-Tur J, Williams J, Owen MJ, Hardy J, Goate AM (2000) Susceptibility locus for Alzheimer's disease on chromosome 10. Science 290:2304–2305

    Google Scholar 

  10. Tucker HM, Kihiko M, Caldwell JN, Wright S, Kawarabayashi T, Price D, Walker D, Scheff S, McGillis JP, Rydel RE, Estus S (2000) The plasmin system is induced by and degrades amyloid-beta aggregates. J Neurosci 20:3937–3946

    Google Scholar 

  11. Ledesma MD, Da Silva JS, Crassaerts K, Delacourte A, De Strooper B, Dotti CG (2000) Brain plasmin enhances APP alpha-cleavage and Abeta degradation and is reduced in Alzheimer's disease brains. EMBO Rep 1:530–535

    Google Scholar 

  12. Buss S, Muller-Thomsen T, Hock C, Alberici A, Binetti G, Nitsch RM, Gal A, Finckh U (2002) No association between DCP1 genotype and late-onset Alzheimer disease. Am J Med Genet 114:440–445

    Google Scholar 

  13. Finckh U, Kammer H von der, Velden J, Michel T, Andresen B, Deng A, Zhang J, Muller-Thomsen T, Zuchowski K, Menzer G, Mann U, Papassotiropoulos A, Heun R, Zurdel J, Holst F, Benussi L, Stoppe G, Reiss J, Miserez AR, Staehelin HB, Rebeck GW, Hyman BT, Binetti G, Hock C, Growdon JH, Nitsch RM (2000) Genetic association of a cystatin C gene polymorphism with late-onset Alzheimer disease. Arch Neurol 57:1579–1583

    Google Scholar 

  14. Menzer G, Muller-Thomsen T, Meins W, Alberici A, Binetti G, Hock C, Nitsch RM, Stoppe G, Reiss J, Finckh U (2001) Non-replication of association between cathepsin D genotype and late onset Alzheimer disease. Am J Med Genet 105:179–182

    Google Scholar 

  15. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34:939–944

    Google Scholar 

  16. Folstein MF, Folstein SE, McHugh PR (1975) "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198

    Google Scholar 

  17. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, Duijn CM van (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. Jama 278:1349–1356

    Google Scholar 

  18. Conne B, Berczy M, Belin D (1997) Detection of polymorphisms in the human urokinase-type plasminogen activator gene. Thromb Haemost 77:434–435

    Google Scholar 

  19. Turkmen B, Schmitt M, Schmalfeldt B, Trommler P, Hell W, Creutzburg S, Graeff H, Magdolen V (1997) Mutational analysis of the genes encoding urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 in advanced ovarian cancer. Electrophoresis 18:686–689

    Google Scholar 

Download references

Acknowledgement

This work was supported by grants FI 704/1–3 and FOR 267 of the Deutsche Forschungsgemeinschaft.

Author information

Author notes

  1. G. Stoppe

    Present address: Psychiatrische Universitätsklinik Basel, Switzerland

Authors and Affiliations

  1. Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

    U. Finckh, K. van Hadeln & A. Gal

  2. Psychiatrische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

    T. Müller-Thomsen

  3. Scientific Institute for Research and Patient Care, S. Giovanni di Dio, Brescia, Italy

    A. Alberici & G. Binetti

  4. Division of Psychiatry Research, University of Zürich, Switzerland

    C. Hock & R. M. Nitsch

  5. Psychiatrische Klinik, Institut für Humangenetik, Universität Göttingen, Germany

    G. Stoppe

  6. Institut für Humangenetik, Universität Göttingen, Germany

    J. Reiss

  7. Universitätsklinikum Hamburg-Eppendorf, Institut für Humangenetik, Butenfeld 42, 22529 Hamburg, Germany

    U. Finckh

Authors
  1. U. Finckh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. van Hadeln
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. Müller-Thomsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Alberici
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. Binetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C. Hock
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R. M. Nitsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G. Stoppe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J. Reiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A. Gal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to U. Finckh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Finckh, U., van Hadeln, K., Müller-Thomsen, T. et al. Association of late-onset Alzheimer disease with a genotype of PLAU, the gene encoding urokinase-type plasminogen activator on chromosome 10q22.2. Neurogenetics 4, 213–217 (2003). https://doi.org/10.1007/s10048-003-0157-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10048-003-0157-9

Keywords

Search

Navigation