A functional polymorphism within plasminogen activator urokinase (PLAU) is associated with Alzheimer's disease

Matthias Riemenschneider; Lidija Konta; Patricia Friedrich; Sandra Schwarz; Kevin Taddei; Frauke Neff; Alessandro Padovani; Heike Kölsch; Simon M. Laws; Norman Klopp; Heike Bickeböller; Stefan Wagenpfeil; Jakob C. Mueller; Albert Rosenberger; Janine Diehl-Schmid; Silvana Archetti; Nicola Lautenschlager; Barbara Borroni; Ulrich Müller; Thomas Illig; Reinhard Heun; Rupert Egensperger; Jürgen Schlegel; Hans Förstl; Ralph N. Martins; Alexander Kurz; M. Krömmer; B. Cramer; A. Klimbacher; P. Belcredi; G. Laux; Eberl; H. E. Klein; Bernd Ibach; Eberhard Koenig; Barbara Romero; Manfred Wolfersdorf; Michael Schüler; Mathias Berger; Schmidtke; E. Jost; M. Schmauss; Ch Steber; R. Heinrich; Wiegele Britta; H. P. Volz; M. Jähnel; M. Dose; Macquard; Bremer; N. Braunisch; H. Nickl; L. Blaha; S. Herpich; H. W. Dietl; R. Schüttler; R. Hess; M. Philipp; A. Wermuth

doi:10.1093/hmg/ddl167

A functional polymorphism within plasminogen activator urokinase (PLAU) is associated with Alzheimer's disease

Matthias Riemenschneider^*, Lidija Konta, Patricia Friedrich, Sandra Schwarz, Kevin Taddei, Frauke Neff, Alessandro Padovani, Heike Kölsch, Simon M. Laws, Norman Klopp, Heike Bickeböller, Stefan Wagenpfeil, Jakob C. Mueller, Albert Rosenberger, Janine Diehl-Schmid, Silvana Archetti, Nicola Lautenschlager, Barbara Borroni, Ulrich Müller, Thomas IlligReinhard Heun, Rupert Egensperger, Jürgen Schlegel, Hans Förstl, Ralph N. Martins, Alexander Kurz, M. Krömmer, B. Cramer, A. Klimbacher, P. Belcredi, G. Laux, Eberl, H. E. Klein, Bernd Ibach, Eberhard Koenig, Barbara Romero, Manfred Wolfersdorf, Michael Schüler, Mathias Berger, Schmidtke, E. Jost, M. Schmauss, Ch Steber, R. Heinrich, Wiegele Britta, H. P. Volz, M. Jähnel, M. Dose, Macquard, Bremer, N. Braunisch, H. Nickl, L. Blaha, S. Herpich, H. W. Dietl, R. Schüttler, R. Hess, M. Philipp, A. Wermuth

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

39 Citations (Scopus)

Abstract

A number of susceptibility loci for Alzheimer's disease (AD) have been identified including a region on Chromosome 10q21-22. Within this region the plasminogen activator urokinase gene (PLAU) was considered as a reasonable candidate from its functional implication in plasmin generation, a serine protease capable of degrading beta-Amyloid (Aβ) protein. We screened 56 single nucleotide polymorphisms (SNPs) around PLAU using 1751 individuals from four independent case-control samples (Munich, N = 679; Bonn N = 282; Brescia (Italy) N = 219; Perth (Australia) N = 557 and one discordant sib-pair sample (Munich N = 622). In brain tissue samples of neuropathologically confirmed cases with AD (N = 33) we analyzed plaque counts according to the risk allele. We identified that one functional exonic SNP (rs2227564) is associated with development of AD using the four independent case-control samples (Munich, P = 0.02; Bonn, P = 0.005; Brescia (Italy), P = 0.001; Perth (Australia), P = 0.03) and the discordant sib-pair sample (P = 0.001). In brain tissue, from neuropathologically confirmed cases with AD, we identified significantly higher plaque counts in carriers of the risk allele (N = 6; 60.3 ± 16.9) compared with non-carriers (N = 9; 26.3±8.8; P = 0.007). This study provides compelling evidence of a genetic and functional involvement of a common PLAU variant into the pathogenesis of AD. Further functional investigations are warranted to elucidate the specific role of PLAU, respectively, PLAU variants in the metabolism of Aβ proteins.

Original language	English
Pages (from-to)	2446-2456
Number of pages	11
Journal	Human Molecular Genetics
Volume	15
Issue number	16
DOIs	https://doi.org/10.1093/hmg/ddl167
Publication status	Published - 15 Aug 2006
Externally published	Yes

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Riemenschneider, M., Konta, L., Friedrich, P., Schwarz, S., Taddei, K., Neff, F., Padovani, A., Kölsch, H., Laws, S. M., Klopp, N., Bickeböller, H., Wagenpfeil, S., Mueller, J. C., Rosenberger, A., Diehl-Schmid, J., Archetti, S., Lautenschlager, N., Borroni, B., Müller, U., ... Wermuth, A. (2006). A functional polymorphism within plasminogen activator urokinase (PLAU) is associated with Alzheimer's disease. Human Molecular Genetics, 15(16), 2446-2456. https://doi.org/10.1093/hmg/ddl167

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title = "A functional polymorphism within plasminogen activator urokinase (PLAU) is associated with Alzheimer's disease",

abstract = "A number of susceptibility loci for Alzheimer's disease (AD) have been identified including a region on Chromosome 10q21-22. Within this region the plasminogen activator urokinase gene (PLAU) was considered as a reasonable candidate from its functional implication in plasmin generation, a serine protease capable of degrading beta-Amyloid (Aβ) protein. We screened 56 single nucleotide polymorphisms (SNPs) around PLAU using 1751 individuals from four independent case-control samples (Munich, N = 679; Bonn N = 282; Brescia (Italy) N = 219; Perth (Australia) N = 557 and one discordant sib-pair sample (Munich N = 622). In brain tissue samples of neuropathologically confirmed cases with AD (N = 33) we analyzed plaque counts according to the risk allele. We identified that one functional exonic SNP (rs2227564) is associated with development of AD using the four independent case-control samples (Munich, P = 0.02; Bonn, P = 0.005; Brescia (Italy), P = 0.001; Perth (Australia), P = 0.03) and the discordant sib-pair sample (P = 0.001). In brain tissue, from neuropathologically confirmed cases with AD, we identified significantly higher plaque counts in carriers of the risk allele (N = 6; 60.3 ± 16.9) compared with non-carriers (N = 9; 26.3±8.8; P = 0.007). This study provides compelling evidence of a genetic and functional involvement of a common PLAU variant into the pathogenesis of AD. Further functional investigations are warranted to elucidate the specific role of PLAU, respectively, PLAU variants in the metabolism of Aβ proteins.",

author = "Matthias Riemenschneider and Lidija Konta and Patricia Friedrich and Sandra Schwarz and Kevin Taddei and Frauke Neff and Alessandro Padovani and Heike K{\"o}lsch and Laws, {Simon M.} and Norman Klopp and Heike Bickeb{\"o}ller and Stefan Wagenpfeil and Mueller, {Jakob C.} and Albert Rosenberger and Janine Diehl-Schmid and Silvana Archetti and Nicola Lautenschlager and Barbara Borroni and Ulrich M{\"u}ller and Thomas Illig and Reinhard Heun and Rupert Egensperger and J{\"u}rgen Schlegel and Hans F{\"o}rstl and Martins, {Ralph N.} and Alexander Kurz and M. Kr{\"o}mmer and B. Cramer and A. Klimbacher and P. Belcredi and G. Laux and Eberl and Klein, {H. E.} and Bernd Ibach and Eberhard Koenig and Barbara Romero and Manfred Wolfersdorf and Michael Sch{\"u}ler and Mathias Berger and Schmidtke and E. Jost and M. Schmauss and Ch Steber and R. Heinrich and Wiegele Britta and Volz, {H. P.} and M. J{\"a}hnel and M. Dose and Macquard and Bremer and N. Braunisch and H. Nickl and L. Blaha and S. Herpich and Dietl, {H. W.} and R. Sch{\"u}ttler and R. Hess and M. Philipp and A. Wermuth",

year = "2006",

month = aug,

day = "15",

doi = "10.1093/hmg/ddl167",

language = "English",

volume = "15",

pages = "2446--2456",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "16",

}

Riemenschneider, M, Konta, L, Friedrich, P, Schwarz, S, Taddei, K, Neff, F, Padovani, A, Kölsch, H, Laws, SM, Klopp, N, Bickeböller, H, Wagenpfeil, S, Mueller, JC, Rosenberger, A, Diehl-Schmid, J, Archetti, S, Lautenschlager, N, Borroni, B, Müller, U, Illig, T, Heun, R, Egensperger, R, Schlegel, J, Förstl, H, Martins, RN, Kurz, A, Krömmer, M, Cramer, B, Klimbacher, A, Belcredi, P, Laux, G, Eberl, Klein, HE, Ibach, B, Koenig, E, Romero, B, Wolfersdorf, M, Schüler, M, Berger, M, Schmidtke, Jost, E, Schmauss, M, Steber, C, Heinrich, R, Britta, W, Volz, HP, Jähnel, M, Dose, M, Macquard, Bremer, Braunisch, N, Nickl, H, Blaha, L, Herpich, S, Dietl, HW, Schüttler, R, Hess, R, Philipp, M & Wermuth, A 2006, 'A functional polymorphism within plasminogen activator urokinase (PLAU) is associated with Alzheimer's disease', Human Molecular Genetics, vol. 15, no. 16, pp. 2446-2456. https://doi.org/10.1093/hmg/ddl167

TY - JOUR

T1 - A functional polymorphism within plasminogen activator urokinase (PLAU) is associated with Alzheimer's disease

AU - Riemenschneider, Matthias

AU - Konta, Lidija

AU - Friedrich, Patricia

AU - Schwarz, Sandra

AU - Taddei, Kevin

AU - Neff, Frauke

AU - Padovani, Alessandro

AU - Kölsch, Heike

AU - Laws, Simon M.

AU - Klopp, Norman

AU - Bickeböller, Heike

AU - Wagenpfeil, Stefan

AU - Mueller, Jakob C.

AU - Rosenberger, Albert

AU - Diehl-Schmid, Janine

AU - Archetti, Silvana

AU - Lautenschlager, Nicola

AU - Borroni, Barbara

AU - Müller, Ulrich

AU - Illig, Thomas

AU - Heun, Reinhard

AU - Egensperger, Rupert

AU - Schlegel, Jürgen

AU - Förstl, Hans

AU - Martins, Ralph N.

AU - Kurz, Alexander

AU - Krömmer, M.

AU - Cramer, B.

AU - Klimbacher, A.

AU - Belcredi, P.

AU - Laux, G.

AU - Eberl,

AU - Klein, H. E.

AU - Ibach, Bernd

AU - Koenig, Eberhard

AU - Romero, Barbara

AU - Wolfersdorf, Manfred

AU - Schüler, Michael

AU - Berger, Mathias

AU - Schmidtke,

AU - Jost, E.

AU - Schmauss, M.

AU - Steber, Ch

AU - Heinrich, R.

AU - Britta, Wiegele

AU - Volz, H. P.

AU - Jähnel, M.

AU - Dose, M.

AU - Macquard,

AU - Bremer,

AU - Braunisch, N.

AU - Nickl, H.

AU - Blaha, L.

AU - Herpich, S.

AU - Dietl, H. W.

AU - Schüttler, R.

AU - Hess, R.

AU - Philipp, M.

AU - Wermuth, A.

PY - 2006/8/15

Y1 - 2006/8/15

N2 - A number of susceptibility loci for Alzheimer's disease (AD) have been identified including a region on Chromosome 10q21-22. Within this region the plasminogen activator urokinase gene (PLAU) was considered as a reasonable candidate from its functional implication in plasmin generation, a serine protease capable of degrading beta-Amyloid (Aβ) protein. We screened 56 single nucleotide polymorphisms (SNPs) around PLAU using 1751 individuals from four independent case-control samples (Munich, N = 679; Bonn N = 282; Brescia (Italy) N = 219; Perth (Australia) N = 557 and one discordant sib-pair sample (Munich N = 622). In brain tissue samples of neuropathologically confirmed cases with AD (N = 33) we analyzed plaque counts according to the risk allele. We identified that one functional exonic SNP (rs2227564) is associated with development of AD using the four independent case-control samples (Munich, P = 0.02; Bonn, P = 0.005; Brescia (Italy), P = 0.001; Perth (Australia), P = 0.03) and the discordant sib-pair sample (P = 0.001). In brain tissue, from neuropathologically confirmed cases with AD, we identified significantly higher plaque counts in carriers of the risk allele (N = 6; 60.3 ± 16.9) compared with non-carriers (N = 9; 26.3±8.8; P = 0.007). This study provides compelling evidence of a genetic and functional involvement of a common PLAU variant into the pathogenesis of AD. Further functional investigations are warranted to elucidate the specific role of PLAU, respectively, PLAU variants in the metabolism of Aβ proteins.

AB - A number of susceptibility loci for Alzheimer's disease (AD) have been identified including a region on Chromosome 10q21-22. Within this region the plasminogen activator urokinase gene (PLAU) was considered as a reasonable candidate from its functional implication in plasmin generation, a serine protease capable of degrading beta-Amyloid (Aβ) protein. We screened 56 single nucleotide polymorphisms (SNPs) around PLAU using 1751 individuals from four independent case-control samples (Munich, N = 679; Bonn N = 282; Brescia (Italy) N = 219; Perth (Australia) N = 557 and one discordant sib-pair sample (Munich N = 622). In brain tissue samples of neuropathologically confirmed cases with AD (N = 33) we analyzed plaque counts according to the risk allele. We identified that one functional exonic SNP (rs2227564) is associated with development of AD using the four independent case-control samples (Munich, P = 0.02; Bonn, P = 0.005; Brescia (Italy), P = 0.001; Perth (Australia), P = 0.03) and the discordant sib-pair sample (P = 0.001). In brain tissue, from neuropathologically confirmed cases with AD, we identified significantly higher plaque counts in carriers of the risk allele (N = 6; 60.3 ± 16.9) compared with non-carriers (N = 9; 26.3±8.8; P = 0.007). This study provides compelling evidence of a genetic and functional involvement of a common PLAU variant into the pathogenesis of AD. Further functional investigations are warranted to elucidate the specific role of PLAU, respectively, PLAU variants in the metabolism of Aβ proteins.

UR - http://www.scopus.com/inward/record.url?scp=33747884644&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddl167

DO - 10.1093/hmg/ddl167

M3 - Article

C2 - 16825285

AN - SCOPUS:33747884644

SN - 0964-6906

VL - 15

SP - 2446

EP - 2456

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 16

ER -

A functional polymorphism within plasminogen activator urokinase (PLAU) is associated with Alzheimer's disease

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