Evidence for induction of the ornithine transcarbamylase expression in Alzheimer's disease.
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 -389 G/A and -241 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.
Bensemain
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F
INSERM, U744, Institut Pasteur de Lille, Université de Lille 2, Lille, France.
Hot
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Ferreira
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Dumont
J
J
Bombois
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Maurage
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CA
Huot
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Hermant
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Levillain
E
E
Hubans
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Hansmannel
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Chapuis
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Hauw
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Schraen
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Lemoine
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Buée
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Berr
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Mann
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Pasquier
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Amouyel
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Lambert
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D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000378:metabolism; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D005838:Genotype; D006801:Humans; D008297:Male; D046228:Microarray Analysis / Q000379:methods; D009954:Ornithine Carbamoyltransferase / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors
D009954:Ornithine Carbamoyltransferase