Promoter Mutations That Increase Amyloid Precursor-Protein Expression Are Associated with Alzheimer Disease (original) (raw)
Related papers
Variations in the APP gene promoter region and risk of Alzheimer disease
Neurology, 2007
We genotyped five polymorphisms, including two polymorphisms with known effects on transcriptional activity, in a large cohort of 427 Alzheimer disease (AD) cases and 472 control subjects. An association between rs463946 (Ϫ3102 G/C) and AD was found and was confirmed in a replication sample of a similar size. By contrast, analysis of three recently described rare mutations influencing APP transcription did not confirm their association with AD risk.
Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease
Brain, 2006
It is well established that Alzheimer's disease causing mutations in APP, PSEN1 and PSEN2 lead to a relative increased production of Ab 42 , thereby fostering its deposition in plaques. Recently others and we showed that amyloid precursor protein (APP) overproduction, either as a result of genomic locus duplication or altered regulatory sequences in the APP promoter region, leads to early-onset disease. Here, we have expanded our study of genetic variability in the APP promoter to a large group of well-documented Belgian patients (n = 750, mean onset age = 75.0 6 8.6, range = 37-96). We identified three different APP promoter mutations (À369C!G, À534G!A and À479C!T) in seven patients. In patients with onset <70 years (n = 204), we identified one patient carrying the London APP V717I mutation while no patients carried an APP locus duplication, indicating that APP promoter mutations (n = 2) were more frequently associated with increased risk for early-onset Alzheimer's disease. The two mutations (À369C!G and À534G!A) increasing APP promoter activity by nearly 2-fold and mimicking an APP duplication, appeared in probands of families with multiple patients with dementia. The À479C!T mutation that increased APP expression only mildly (1.2-fold), was observed in four patients with onset ages ranging from 62 to 79 years (mean 71.5 years), suggesting that its contribution to disease risk is more pronounced at later age due to modulating factors. In conclusion, we provided evidence that mutations in APP regulatory sequences are more frequent than APP coding mutations, and that increased APP transcriptional activity constitutes a risk factor for Alzheimer's disease with onset ages inversely correlated with levels of APP expression.
The FASEB Journal, 2005
Alzheimer's disease is characterized by brain deposition of toxic amyloid beta-peptide (Abeta), generated from the Abeta precursor protein (APP). APP gene expression is regulated via the proximal promoter region (PPR; -46/-1 in the human sequence; +1 transcription start) and the 5'-untranslated region (5'-UTR; +1/+147). We have recently identified a unique CAGA sequence, "amyloid" (+83/+86) present only in the APP gene from amyloid plaque-forming species, absent in all APP-like-proteins' (APLP1 and APLP2) genes. To assay functional activity of PPR + UTR and 5'-UTR regions that either contain or lack the "amyloid" box, we tested nine constructs in transient transfection studies. We observed significantly high reporter gene activity with -46/144, -46/100, -46/54, and 54/144 constructs. The 54/100 fragment, which contains a transforming growth factor-beta/ "amyloid"/interleukin-1 acute box cassette, showed different activity depending o...
The FASEB Journal, 2005
Alzheimer's disease is characterized by brain deposition of toxic amyloid β-peptide (Aβ), generated from the Aβ precursor protein (APP). APP gene expression is regulated via the proximal promoter region (PPR; −46/−1 in the human sequence; +1 transcription start) and the 5′-untranslated region (5′-UTR; +1/+147). We have recently identified a unique CAGA sequence, "amyloid," (+83/+86) present only in the APP gene from amyloid plaque-forming species, absent in all APP-like-proteins' (APLP1 and APLP2) genes. To assay functional activity of PPR + UTR and 5′-UTR regions that either contain or lack the "amyloid" box, we tested nine constructs in transient transfection studies. We observed significantly high reporter gene activity with −46/144, −46/100, −46/54, and 54/144 constructs. The 54/100 fragment, which contains a transforming growth factor-β/"amyloid"/interleukin-1 acute box cassette, showed different activity depending on cell type. Electrophoretic mobility shift assay (EMSA) showed distinct DNA-nuclear protein interaction in all fragments, differing among both cell types and specific fragment. Reporter gene expression corroborates with the DNA-protein binding pattern. To directly examine the "amyloid" box, we generated oligomers for CAGA mutants or mutated adjacent nucleotides. EMSA results showed that altering "amyloid" or adjacent sequence alters specific DNA-nuclear protein interaction in both mutation-and cell-type-specific manners. Reporter gene assay reveals mutant-specific expression effects. Therefore, the −46/54 region appears to be essential for basal expression of the APP gene, the 54/100 and 100/144 regions may have tissue-specific activity, and the "amyloid" CAGA box plays a role in APP gene regulation.
The coding sequence of amyloid-β precursor protein APP contains a neural-specific promoter element
Brain Research, 2006
The amyloid-β precursor protein APP is generally accepted to be involved in the pathology of Alzheimer's disease. Since its physiological role is still unclear, we decided to study the function of APP via stable transgenesis in the amphibian Xenopus laevis. However, the application of constructs encoding (mutant) APP fused to the C-terminus of the green fluorescent protein GFP (GFP-APP), and harboring a tissue-specific or an inducible gene promoter did not result in transgene expression of APP in neuronal and neuroendocrine cells. Surprisingly, a construct encoding either Xenopus or human APP fused to the Nterminus of GFP (APP-GFP) gave fluorescence throughout the whole brain of the tadpole, despite the fact that a proopiomelanocortin gene promoter was used to target transgene expression specifically to the intermediate pituitary cells. Detailed analysis with deletion mutants revealed the presence of a neural-specific, transcriptionally active DNA element within the 3′-end of the APP-coding sequence that gave rise to an aberrant transcript and protein in the APP-GFP transgenic animals. The DNA element appears to prevent proper APP transgene expression in Xenopus neuronal and neuroendocrine cells. Thus, the coding sequences of Xenopus and human APP contain a neural-specific promoter element, the physiological significance of which is at present unclear.
Role of common and rare APP DNA sequence variants in Alzheimer disease
Neurology, 2012
Objectives: More than 30 different rare mutations, including copy number variants (CNVs), in the amyloid precursor protein gene (APP) cause early-onset familial Alzheimer disease (EOFAD), whereas the contribution of common APP variants to disease risk remains controversial. In this study we systematically assessed the role of both rare and common APP DNA variants in Alzheimer disease (AD) families.
Transcriptional regulation of Alzheimer's disease genes: implications for susceptibility
Human Molecular Genetics, 2000
In recent years, important progress has been made in uncovering genes implicated in Alzheimer's disease (AD). Three causal genes have been identified in which mutations cause familial presenile AD: the amyloid precursor protein gene and the presenilin 1 and 2 genes. Additionally, the ε4 allele of the apolipoprotein E gene was shown to be a major risk factor for AD. Despite the genetic heterogeneity, all of these genes work through a common mechanism, i.e. increasing the amount and deposition of the amyloid β peptide (Aβ) in brain triggering AD-related neuronal degeneration. Therefore, the levels of Aβ and of the factors involved in its production and deposition are important in the neuropathogenesis of AD. Regulation of transcription of AD genes might therefore be an important player in the neurodegenerative process. In this review, we describe the major features of transcriptional regulation of the known AD genes and the implications of variable expression levels on susceptibility to AD.
Amyloid Precursor Protein Gene ( APP ) Variation in Late-Onset Alzheimer’s Disease
Journal of Molecular Neuroscience
Mutations in the beta-amyloid precursor protein gene (APP) have been found in familial early-onset Alzheímer’s disease (AD). DNA variants at several genes have been linked to the risk of developing the most common late-onset form of AD (LOAD). A few studies analyzed the contribution of APP variants to LOAD, with negative or conflicting results. We determined the variation in the 18 APP exons and flanking intronic sequences in a total of 350 LOAD patients from Spain. A total of 13 nucleotide changes were found and 6 were new and not found among 340 healthy controls, including the only missense change (D243N). The in silico analysis suggested that none of them would have an effect on pre-mRNA splicing or protein folding (D243N). Patients and controls were also genotyped for three APP promoter polymorphisms, and none of them was significantly associated with LOAD. We concluded that APP variants would not contribute to the risk of developing LOAD in our population.
Journal of Biological Chemistry
A manifestation of Alzheimer's disease is the presence of amyloid depositions in brains of afflicted individuals. A major component of these depositions is the amyloid beta-protein, which is a truncated form of the larger amyloid beta-protein precursor (APP). To investigate the regulation of APP gene expression, the APP promoter and selected deletions were placed 5' to the reporter gene chloramphenicol acetyltransferase. The promoter deletions were transfected into different cell lines that showed variant levels of endogenous APP transcripts. Transient transfection assays showed that 96 base pairs 5' to the transcriptional start site are sufficient for cell type-specific promoter activity. A nuclear factor that binds to this region in a sequence-specific manner was identified by mobility shift electrophoresis, DNase footprinting, and methylation interference. The DNase-protected region covers about 25 base pairs on both strands (position -31 to -55). Mutations within thi...
Molecular Brain Research, 1995
Familial (autosomal dominant) Alzheimer's disease (FAD) is a genetically heterogeneous disorder. Mutations in exons 16 and 17 of the amyloid/3-protein precursor (flPP) gene currently account for less than 2% of FAD kindreds. No known defect in/3PP quantity, structure, or processing accounts for disease-associated fl-amyloid deposition in the majority of early-onset FAD kindreds. Only two out of a sample of 48 pedigrees (particularly the early onset FAD 4 kindred) contributed noticeably to evidence of linkage at the D21S16/13 and S1/Sll loci in the chromosomal region 21q21 . Many early onset FAD pedigrees (including the FAD 1 and FAD 4 kindreds) show strong evidence of linkage to markers in the chromosome 14q24.3 region. Patients with trisomy 21 (Down's syndrome, DS) virtually always develop a histopathological phenotype indistinguishable from FAD, presumably on the basis of increased /3PP gene dosage and transcription. Whereas no /3PP gene duplication has been found in FAD, other mechanisms that augment/3PP production by effects at the transcriptional level could explain some FAD cases. Here, we report that cultured fibroblasts from affected members of the FAD 1 pedigree show a = 1.9 fold increase (P = 0.007) in flPP mRNA levels compared to unaffected members when the cells are grown under stressed conditions in 0.5% serum. The elevated levels of/~PP mRNA in cells cultured in 0.5% serum also cosegregate with haplotypes in the 14q24.3 region when analyzed by linkage methods (LOD score = 3.26 at 0 = 0.001). This is the chromosomal region to which FAD in this family has previously been mapped. As expected, fibroblasts from patients with DS used as a control show a similar /3PP mRNA increase. Fibroblasts from the FAD 4 pedigree did not show this defect under the conditions utilized here. flPP and A/3 protein levels were determined quantitatively after metabolic labeling and immunoprecipitation and found to increase 2.0 and 2.5 fold, respectively, in the fibroblasts from affected FAD 1 members. Finally, transient transfections of a /3PP promoter/chloramphenicol acetyl transferase reporter gene construct demonstrated a = 3-4 fold increase in/3PP promoter activity in affected fibroblasts from the FAD 1 but not the FAD 4 pedigree. Taken together, these data raise the possibility that an increase in/3PP transcription may underlie the AD phenotype in at least some of the chromosome 14-1inked FAD families.