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

Ertekin-Taner, Nilüfer; Ronald, James; Feuk, Lars; Prince, Jonathan A.; Tucker, Michael; Younkin, Linda H.; Hella, Maria; Jain, Sandeep; Hackett, Alyssa M.; Scanlin, Leah; Kelly, Jason; Kihiko-Ehman, Muthoni; Neltner, Matthew; Hersh, Louis B.; Kindy, Mark S.; Markesbery, William R.; Hutton, Michael; Andrade, Mariza de; Petersen, Ronald C.; Graff‐Radford, Neill R.; Estus, Steve; Brookes, Anthony J.; Younkin, Steven G.

doi:10.1093/hmg/ddi041

Cited by 63 publications

(60 citation statements)

References 32 publications

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“…It is also possible that activation of uPA, a functional analog of tPA (19,30), contributes to efficacy in our experiments, because PAI-1 is also the principal inhibitor of uPA. This may be of relevance given that single nucleotide polymorphisms in the uPA gene have been associated with elevated A␤ 42 levels in the plasma of patients with late onset AD (31).…”

Section: Discussionmentioning

confidence: 97%

Enhanced clearance of Aβ in brain by sustaining the plasmin proteolysis cascade

Js¹,

Ta²,

Martone³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

131

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The amyloid hypothesis states that a variety of neurotoxic ␤-amyloid (A␤) species contribute to the pathogenesis of Alzheimer's disease. Accordingly, a key determinant of disease onset and progression is the appropriate balance between A␤ production and clearance. Enzymes responsible for the degradation of A␤ are not well understood, and, thus far, it has not been possible to enhance A␤ catabolism by pharmacological manipulation. We provide evidence that A␤ catabolism is increased after inhibition of plasminogen activator inhibitor-1 (PAI-1) and may constitute a viable therapeutic approach for lowering brain A␤ levels. PAI-1 inhibits the activity of tissue plasminogen activator (tPA), an enzyme that cleaves plasminogen to generate plasmin, a protease that degrades A␤ oligomers and monomers. Because tPA, plasminogen and PAI-1 are expressed in the brain, we tested the hypothesis that inhibitors of PAI-1 will enhance the proteolytic clearance of brain A␤. Our data demonstrate that PAI-1 inhibitors augment the activity of tPA and plasmin in hippocampus, significantly lower plasma and brain A␤ levels, restore long-term potentiation deficits in hippocampal slices from transgenic A␤-producing mice, and reverse cognitive deficits in these mice.Alzheimer ͉ plasminogen activator inhibitor ͉ tissue plasminogen activator A lzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of intracellular neuronal tangles and extracellular parenchymal and vascular amyloid deposits containing ␤-amyloid peptide (A␤). A␤ is a 39-to 42-aa peptide derived from the proteolytic processing of the amyloid precursor protein (APP) (1). The ''amyloid hypothesis'' of AD postulates a central causal role for A␤ in AD pathogenesis and is supported by genetic and physiological evidence. All known early onset familial AD mutations result in enhanced levels of cytotoxic A␤ species, amyloid plaque deposition, and dementia. Furthermore, A␤ peptide is reported to be neurotoxic and synaptotoxic in vitro and in vivo, inhibiting long-term potentiation (LTP), a physiological correlate of memory (2). Based on these observations, a number of strategies to reduce brain A␤ levels are being pursued as therapeutic approaches to treat AD (3, 4).If the amyloid hypothesis of AD is correct and A␤ levels are pivotal to disease etiology, then the balance between A␤ production and catabolism is likely to be a key determinant of disease progression. It has been suggested that insufficient clearance of A␤ may account for elevated A␤ levels in the brain and the accumulation of pathogenic amyloid deposits in sporadic AD (5). A number of proteases have been implicated in the proteolytic clearance of A␤ from the CNS, including neprilysin, insulin-degrading enzyme, endothelin converting enzyme, and plasmin (3, 6-8). The relative contribution of these enzymes to A␤ catabolism remains unclear, but each protease may play a significant role in the degradation and clearance of A␤, resulting in a slowing of A␤ accumulation and aggregation and u...

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Section: Discussionmentioning

confidence: 97%

Enhanced clearance of Aβ in brain by sustaining the plasmin proteolysis cascade

Js¹,

Ta²,

Martone³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

131

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“…Although it is common to exclude markers which deviate from HWE from association studies, it is possible to miss true risk factors by doing so. A recent report described such a polymorphism in the urokinasetype plasminogen activator gene associating with Alzheimer's disease (22).…”

Section: Discussionmentioning

confidence: 99%

Refinement of the 22q12-q13 Breast Cancer–Associated Region: Evidence of TMPRSS6 as a Candidate Gene in an Eastern Finnish Population

Hartikainen

Tuhkanen²,

Kataja³

et al. 2006

Clinical Cancer Research

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Although many risk factors for breast cancer are known, most of the genetic background and molecular mechanisms still remain to be elucidated. We have previously published an autosome-wide microsatellite scan for breast cancer association and here we report a follow-up study for one of the detected regions. Ten single nucleotide polymorphisms (SNP) were genotyped in an Eastern Finnish population sample of 497 breast cancer cases and 458 controls to refine the 550-kb region on 22q12-q13 and identify the breast cancer^associated gene(s) in this region. We also studied 22q12-q13 for allelic imbalance for the detection of a possible tumor suppressor gene and to see whether the breast cancer association and allelic imbalance in this region could be connected. A SNP (rs733655) in matriptase-2 gene (TMPRSS6) was detected to associate with breast cancer risk. The genotype frequencies of rs733655 differed significantly between cases and controls in the entire sample and in the geographically and genetically more homogeneous subsample with P = 0.044 and P = 0.0003, respectively. The heterozygous genotype TC was observed to be the risk genotype in both samples (odds ratios, 1.39; 95% confidence intervals, 1.06-1.83 and odds ratios, 2.11; 95 % confidence intervals, 1. 46-3.05). An associated two-marker haplotype involving SNP rs733655 (empirical P = 0.041) provides further evidence for breast cancer risk factor locating on 22q12-q13, possibly being TMPRSS6. Our results suggest that matriptase-2 gene is associated with breast cancer risk in the Eastern Finnish population.

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“…While many positive findings for candidate genes have been reported, which of several recently claimed to be associated with AD (e.g. urokinase plasminogen activator (PLAU) (Finckh et al 2003;Ertekin-Taner et al 2005) and acetyl-coenzyme A acetyltransferase 1 (ACAT1) (Wollmer et al 2003), none exhibit effects as large and consistent as that of the gene encoding apolipoprotein E (APOE) (Strittmatter et al 1993). Metaanalyses of additional candidates have provided relatively strong evidence of association (e.g.…”

Section: Introductionmentioning

confidence: 99%

Towards compendia of negative genetic association studies: an example for Alzheimer disease

et al. 2005

Self Cite

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Most genetic sequence variants that contribute to variability in complex human traits will have small effects that are not readily detectable with population samples typically used in genetic association studies. A potentially valuable tool in the gene discovery process is meta-analysis of the accumulated published data, but in order to be valid these require a sample of studies representative of the true genetic effect and thus hypothetically should include some positive and an abundance of negative reports. A survey of the literature on association studies for Alzheimer disease (AD) from January 2004-April 2005, identified 138 studies, 86 of which reported positive findings other than for apolipoprotein E (APOE), strongly indicative of publication bias. We report here an analysis of 62 genetic markers, tested for association with AD risk as well as for possible effects upon quantitative indices of AD severity (mini-mental state examination scores, age-at-onset, and cerebrospinal fluid (CSF) beta-amyloid (Abeta) and CSF tau proteins). Within this set, only modest signals were present that, with the exception of APOE are easily lost when corrections for multiple hypotheses are applied. In isolation, results are thus broadly negative. Genes studied encompass both novel candidates as well as several recently claimed to be associated with AD (e.g. urokinase plasminogen activator (PLAU) and acetyl-coenzyme A acetyltransferase 1 (ACAT1)). By reporting these data we hope to encourage the publication of gene compendia to guide further studies and aid future meta-analyses aimed at resolving the involvement of genes in complex human traits.

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

Cited by 63 publications

References 32 publications

Enhanced clearance of Aβ in brain by sustaining the plasmin proteolysis cascade

Enhanced clearance of Aβ in brain by sustaining the plasmin proteolysis cascade

Refinement of the 22q12-q13 Breast Cancer–Associated Region: Evidence of TMPRSS6 as a Candidate Gene in an Eastern Finnish Population

Towards compendia of negative genetic association studies: an example for Alzheimer disease

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