Evidence for induction of the ornithine transcarbamylase expression in Alzheimer's disease

Abstract

To more rapidly identify candidate genes located within chromosomal regions of interest defined by genome scan studies in Alzheimer's disease (AD), we have developed a customized microarray containing all the ORFs (n = 2741) located within nine of these regions. Levels of gene expression were assessed in total RNA from brain tissue of 12 controls and 12 AD patients. Of all genes showing differential expression, we focused on the ornithine transcarbamylase (OTC) gene on Xp21.1., a key enzyme of the urea cycle which we found to be expressed in AD brains but not in controls, as confirmed by RT-PCR. We also detected mRNA expression of all the other urea cycle enzymes in AD brains. Immunochemistry experiments revealed that the OTC expression was strictly restricted to vascular endothelial cells in brain. Furthermore, OTC activity was 880% increased in the CSF of probable AD cases compared with controls. We analysed the association of the OTC À389 G/A and À241 A/G promoter polymorphisms with the risk of developing AD. We observed that rare haplotypes may be associated with the risk of AD through a possible modulation of the methylation of the OTC promoter. In conclusion, our results suggest the involvement of a new pathway in AD brains involving the urea cycle.

Genetics of Alzheimer's disease: new evidences for an old hypothesis?

“…In a complementary way, these different observations further confirm the well-documented presence of vascular dysfunctions in AD [54]. Interestingly, systematic transcriptomic approaches have shown that several genes are differentially expressed in the endothelium of brain capillaries in AD cases, relative to controls [55,56]. In particular, characterization of interleukin 33 as a potential genetic determinant of Ab40 secretion in vitro and cerebral amyloid angiopathy (CAA) in the AD brain could support a potentially relevant link between CAA formation, neurovascular dysfunction and alteration of immune cell functions [56].…”

Association of Ornithine Transcarbamylase Gene Polymorphisms With Hypertension and Coronary Artery Vasomotion

“…Indeed, Bensemain et al showed evidence for: (i) an overexpression of OTC in brain vascular endothelial cells from patients with Alzheimer's disease; (ii) a significant association of the rs5963409 minor allele with an increased risk of disease onset; (iii) a putative functional significance of the rs5963409 minor allele as it was shown to abolish methylation of a CpG island within the promoter of the OTC gene. 20 Given the close association between hypertension and Alzheimer's disease, 30 these results are consistent with this study. Nevertheless, it will be necessary to experimentally validate the functional role of the rs5963409 minor allele and to assess the putative effect of the six other SNPs that are in complete LD with the rs5963409 polymorphism.…”

“…Of note, the rs5963409 polymorphism was of particular interest because the corresponding minor allele was shown to abolish the methylation of a CpG island within the promoter. 20 The rs1800321 polymorphism, not fully associated with the haplotype block (r 2 = 0.12), leads to a nonsynonymous substitution (Lys46Arg). Hence, the OTC SNPs selected for the association studies were the rs5963409 and the rs1800321 polymorphisms.…”

Molecular and Biochemical Features of the Mitochondrial Enzyme Ornithine Transcarbamylase: A Possible New Role as a Signaling Factor

“…On the other hand, OTC induction has been observed in vascular endothelial cells in brains of patients with Alzheimer´s disease. The OTC activity in the CSF of Alzheimer´s patients is several times higher than that in control subjects [5].…”