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

M Riemenschneider; L Konta; P Friedrich; S Schwarz; K Taddei; F Neff; A Padovani; H Kolsch; SM Laws; N Klopp; H Bickeboller; S Wagenpfeil; JC Mueller; A Rosenberger; J Diehl-Schmid; S Archetti; N Lautenschlager; B Borroni; U Muller; T Illig; Reinhard Heun; R Egensperger; J Schlegel; H Forstl; RN Martins; A Kurz

doi:10.1093/hmg/ddl167

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

M Riemenschneider, L Konta, P Friedrich, S Schwarz, K Taddei, F Neff, A Padovani, H Kolsch, SM Laws, N Klopp, H Bickeboller, S Wagenpfeil, JC Mueller, A Rosenberger, J Diehl-Schmid, S Archetti, N Lautenschlager, B Borroni, U Muller, T IlligReinhard Heun, R Egensperger, J Schlegel, H Forstl, RN Martins, A Kurz

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Abstract

A number of susceptibility loci for Alzheimer's disease (AD) have been identified including a region on Chromosome 10q21-q22. 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 (Abeta) 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 Abeta 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 - 16 Jun 2006

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Riemenschneider, M., Konta, L., Friedrich, P., Schwarz, S., Taddei, K., Neff, F., Padovani, A., Kolsch, H., Laws, SM., Klopp, N., Bickeboller, H., Wagenpfeil, S., Mueller, JC., Rosenberger, A., Diehl-Schmid, J., Archetti, S., Lautenschlager, N., Borroni, B., Muller, U., ... Kurz, 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-q22. 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 (Abeta) 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 Abeta proteins.",

author = "M Riemenschneider and L Konta and P Friedrich and S Schwarz and K Taddei and F Neff and A Padovani and H Kolsch and SM Laws and N Klopp and H Bickeboller and S Wagenpfeil and JC Mueller and A Rosenberger and J Diehl-Schmid and S Archetti and N Lautenschlager and B Borroni and U Muller and T Illig and Reinhard Heun and R Egensperger and J Schlegel and H Forstl and RN Martins and A Kurz",

year = "2006",

month = jun,

day = "16",

doi = "10.1093/hmg/ddl167",

language = "English",

volume = "15",

pages = "2446--2456",

journal = "Human Molecular Genetics",

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Riemenschneider, M, Konta, L, Friedrich, P, Schwarz, S, Taddei, K, Neff, F, Padovani, A, Kolsch, H, Laws, SM, Klopp, N, Bickeboller, H, Wagenpfeil, S, Mueller, JC, Rosenberger, A, Diehl-Schmid, J, Archetti, S, Lautenschlager, N, Borroni, B, Muller, U, Illig, T, Heun, R, Egensperger, R, Schlegel, J, Forstl, H, Martins, RN & Kurz, 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, M

AU - Konta, L

AU - Friedrich, P

AU - Schwarz, S

AU - Taddei, K

AU - Neff, F

AU - Padovani, A

AU - Kolsch, H

AU - Laws, SM

AU - Klopp, N

AU - Bickeboller, H

AU - Wagenpfeil, S

AU - Mueller, JC

AU - Rosenberger, A

AU - Diehl-Schmid, J

AU - Archetti, S

AU - Lautenschlager, N

AU - Borroni, B

AU - Muller, U

AU - Illig, T

AU - Heun, Reinhard

AU - Egensperger, R

AU - Schlegel, J

AU - Forstl, H

AU - Martins, RN

AU - Kurz, A

PY - 2006/6/16

Y1 - 2006/6/16

N2 - A number of susceptibility loci for Alzheimer's disease (AD) have been identified including a region on Chromosome 10q21-q22. 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 (Abeta) 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 Abeta proteins.

AB - A number of susceptibility loci for Alzheimer's disease (AD) have been identified including a region on Chromosome 10q21-q22. 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 (Abeta) 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 Abeta 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

SN - 1460-2083

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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