The transcriptional factor LBP-1c/CP2/LSF gene on chromosome 12 is a genetic determinant of Alzheimer's disease

Lambert, Jean‐Charles; Goumidi, Louisa; Vrièze, Fabienne Wavrant‐De; Frigard, B.; Harris, Jonathan; Cummings, A.; Coates, John D.; Pasquier, Florence; Cottel, Dominique; Gaillac, Marianne; Clair, David St; Mann, David; Hardy, John; Lendon, Corinne; Amouyel, Philippe; Chartier-Harlin, Marie-Christine

doi:10.1093/oxfordjournals.hmg.a018918

Cited by 72 publications

(71 citation statements)

References 27 publications

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“…16 Polymorphic variation in the CP2 gene has been known to be one of the AD risk factors. 17 We also provide in vivo evidence that the immunoreacitivities for C-terminal fragments (CTFs) of APLP2 detected by C12 antibody, which specifically recognizes the last 12 amino acids of APLP2 and for GSK-3b are significantly upregulated in the AD brains.Results APLP2-ICDs are translocated into the nucleus in a Fe65-dependent manner. At first, we confirmed whether APLP2-ICDs were detectable in the nucleus after transfecting C57 or…”

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confidence: 79%

Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3β expression

et al. 2006

Cell Death Differ

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Amyloid precursor protein (APP) is a member of a gene family that includes two APP-like proteins, APLP1 and 2. Recently, it has been reported that APLP1 and 2 undergo presenilin-dependent c-secretase cleavage, as does APP, resulting in the release of an B6 kDa intracellular C-terminal domain (ICD), which can translocate into the nucleus. In this study, we demonstrate that the APLP2-ICDs interact with CP2/LSF/LBP1 (CP2) transcription factor in the nucleus and induce the expression of glycogen synthase kinase 3b (GSK-3b), which has broad-ranged substrates such as s-and b-catenin. The significance of this finding is substantiated by the in vivo evidence of the increase in the immunoreactivities for the nuclear C-terminal fragments of APLP2, and for GSK-3b in the AD patients' brain. Taken together, these results suggest that APLP2-ICDs contribute to the AD pathogenesis, by inducing GSK-3b expression through the interaction with CP2 transcription factor in the nucleus. The pathology of Alzheimer's disease (AD) is characterized by the deposition of neuritic plaques, of which the principal components are 40 and 42 amino-acid amyloid beta peptides (Ab) derived from amyloid precursor protein (APP). 1 APP belongs to a family of conserved type I transmembrane proteins including Apl-1 in Caenorhabditis elegans, 2 Appl in Drosophila, 3 and APP, 4 APP-like protein 1 (APLP1) 5 and APLP2 6,7 in mammals.APLP1 and 2 display substantial amino-acid and domain homologies with APP. Although they do not have an Ab domain, their intracellular C-terminal domains (ICDs) are highly similar to that of APP. 8 APLP1 is known to be implicated in synaptogenesis, 9,10 and recombinant APLP2 possesses an ability to promote neurite outgrowth. 11 However, their physiological roles in neurons are still not fully understood. In the brains of AD patients, APLP2 immunoreactivity has been detected in a subset of neuritic plaques, 12 suggesting that APLP2 might be involved in the pathogenesis of AD.APLP2 matures through the same secretory/cleavage pathway as APP 7 and previously, APLP1 and 2 were reported to be processed by g-secretase in a presenilin 1-dependent manner. 8,10 The APLP family can be also cleaved by esecretase to generate the ICD composed of the last 50 amino acids of APLPs C-terminus (C50). 13,14 Moreover, the ICDs of APLP1 and APLP2 produced by g-secretase enhanced Fe65-dependent gene transcriptional activation, as have been reported for the APP intracellular domain (AICD). 10 Fe65, which is known to be ones of the adaptor proteins for APP, contains three protein-protein interaction domains, a WW and two phosphotyrosine binding (PTB) domains. The PTB2 domain, which is located in the C-terminal half of the molecule, is responsible for the interaction between Fe65 and the cytosolic tail of APP through the YENPTY domain of APP. 15 Here, we demonstrate that the ICDs of APLP2 (APLP2-ICDs: C57, C50) interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase 3b (GSK-3b) expression, whereas their point mutants with...

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confidence: 79%

Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3β expression

et al. 2006

Cell Death Differ

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“…17 Among its target genes, CP2 appears to regulate the expression of glycogen synthase kinase-3b, 31 which has been implicated in the pathophysiology of both mood disorders and Alzheimer's disease. 8,32,33 In addition, a non-coding polymorphism in the 3 0 -untranslated region of the CP2 gene has been reported to affect the risk of MDD 34 and Alzheimer's disease, 35 both of which aggregate in RE-MDD families. 1 Nonetheless, a degree of caution is warranted in the interpretation of the in silico results, which are sensitive to the threshold settings employed to minimize false positive and false negative results, and which do not always reflect the biological activity of a putative binding site.…”

Section: Discussionmentioning

confidence: 99%

Effects of the G(−656)A variant on CREB1 promoter activity in a neuronal cell line: Interactions with gonadal steroids and stress

Zubenko

Hughes

2008

Mol Psychiatry

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Major depressive disorder (MDD) constitutes a major public health problem worldwide and affects women twice as frequently as men. Previous genetic studies have revealed significant evidence of linkage of the cAMP-responsive element-binding protein 1 (CREB1) gene region (2q33-35) to mood disorders among women from families with recurrent, early-onset MDD (RE-MDD), a severe and familial subtype of MDD. A rare G-to-A transition at position À656 in the CREB1 promoter co-segregates with mood disorders in women from these families, implicating CREB1 as a sex-related susceptibility gene for unipolar mood disorders. In the current study, the functional significance of the CREB1 promoter variant was determined using transfection experiments that employed plasmid constructs containing the wild-type or variant CREB1 promoters coupled to a reporter gene. The results support the hypothesis that the A À656 allele contributes to the development of MDD in women through selective alteration of CREB1 promoter activity by female gonadal steroids in noradrenergic neuronal cells. Furthermore, exaggeration of these effects during a simulated stress condition may be relevant to reported gene-environment interactions that contribute to the emergence of MDD in clinical populations.

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“…16,21 Rademakers et al 21 suggested that the high degree of conservation in this region suggested the presence of functionally important cis-elements, which they subsequently confirmed through luciferase assays. Further, in silico analysis has shown that the allele A of rs242557 abolished putative binding sites for the transcription factor LBP-1c/LSF/CP2, itself implicated in AD risk, 39,40 and the Se-Cys tRNA gene transcription-activating factor. 21 These findings suggest that the SNP rs242557 may confer differential effects on expression, a hypothesis that is given credence by both our findings and those of Rademakers et al 21 However, in the study of Rademakers and et al 21 the G-allele instead of the A resulted in increased luciferase activity, a finding that the authors themselves described as counterintuitive, based on their association of the A allele with disease risk.…”

Section: Discussionmentioning

confidence: 99%

Fine mapping of the MAPT locus using quantitative trait analysis identifies possible causal variants in Alzheimer's disease

et al. 2006

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In addition to senile plaques, neurofibrillary tangles are characteristic of Alzheimer's disease (AD) pathology, suggesting a clear involvement of the microtubule-associated protein tau (MAPT) in AD. Recent findings, suggesting that the H1c haplotype is associated with increased risk, now also implicate MAPT genetically. In this study, we aim to clarify this association by a fine mapping approach using both a traditional phenotypic association analysis and a quantitative trait (QT) analysis using cerebrospinal fluid (CSF) tau protein levels in the German population. Here, we report that both methodologies identify that the H1c haplotype may play important role in AD (AD risk, P = 0.007, uncorrected; CSF tau levels, P = 0.027, uncorrected). Further, the use of a sliding window approach in the QT analysis allowed for the narrowing down of the region where a probable causal variant may be located. The data suggest that this may lie at or within close proximity to the rs242557 single nucleotide polymorphism as association with CSF tau levels seems to be primarily driven by rs242557 in a gene dosagedependent manner (trend model: P = 0.002, uncorrected). These findings provide functional evidence to support the genetic association of MAPT with AD.

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The transcriptional factor LBP-1c/CP2/LSF gene on chromosome 12 is a genetic determinant of Alzheimer's disease

Cited by 72 publications

References 27 publications

Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3β expression

Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3β expression

Effects of the G(−656)A variant on CREB1 promoter activity in a neuronal cell line: Interactions with gonadal steroids and stress

Fine mapping of the MAPT locus using quantitative trait analysis identifies possible causal variants in Alzheimer's disease

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