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Association of alleles carried at TNFA -850 and BAT1 -22 with Alzheimer's disease.

Gnjec A, D'Costa KJ, Laws SM, Hedley R, Balakrishnan K, Taddei K, Martins G, Paton A, Verdile G, Gandy SE, Broe GA, Brooks WS, Bennett H, Piguet O, Price P, Miklossy J, Hallmayer J, McGeer PL, Martins RN - J Neuroinflammation (2008)

Bottom Line: These cytokines are encoded by genes representing several interleukins and TNFA, which are associated with AD.The gene coding for HLA-B associated transcript 1 (BAT1) lies adjacent to TNFA in the central major histocompatibility complex (MHC).BAT1, a member of the DEAD-box family of RNA helicases, appears to regulate the production of inflammatory cytokines associated with AD pathology.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre of Excellence for Alzheimer's Disease Research and Care, Faculty of Computing, Health and Science, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, 6027, WA, Australia. agnjec@cyllene.uwa.edu.au

ABSTRACT

Background: Inflammatory changes are a prominent feature of brains affected by Alzheimer's disease (AD). Activated glial cells release inflammatory cytokines which modulate the neurodegenerative process. These cytokines are encoded by genes representing several interleukins and TNFA, which are associated with AD. The gene coding for HLA-B associated transcript 1 (BAT1) lies adjacent to TNFA in the central major histocompatibility complex (MHC). BAT1, a member of the DEAD-box family of RNA helicases, appears to regulate the production of inflammatory cytokines associated with AD pathology. In the current study TNFA and BAT1 promoter polymorphisms were analysed in AD and control cases and BAT1 mRNA levels were investigated in brain tissue from AD and control cases.

Methods: Genotyping was performed for polymorphisms at positions -850 and -308 in the proximal promoter of TNFA and position -22 in the promoter of BAT1. These were investigated singly or in haplotypic association in a cohort of Australian AD patients with AD stratified on the basis of their APOE epsilon4 genotype. Semi-quantitative RT-PCR was also performed for BAT1 from RNA isolated from brain tissue from AD and control cases.

Results: APOE epsilon4 was associated with an independent increase in risk for AD in individuals with TNFA -850*2, while carriage of BAT1 -22*2 reduced the risk for AD, independent of APOE epsilon4 genotype. Semi-quantitative mRNA analysis in human brain tissue showed elevated levels of BAT1 mRNA in frontal cortex of AD cases.

Conclusion: These findings lend support to the application of TNFA and BAT1 polymorphisms in early diagnosis or risk assessment strategies for AD and suggest a potential role for BAT1 in the regulation of inflammatory reactions in AD pathology.

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Semi-quantitative RT-PCR of BAT1 and DDXL mRNA in frontal cortex of AD (n = 12) and control cases (n = 16). Data is represented as Box-plots showing median values and quartiles. (A) BAT1 mRNA levels normalized against β-ACTIN (Mann-Whitney U test: *P = .037), (B) BAT1 mRNA levels normalized against GAPDH (Mann-Whitney U test: **P = .057).
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Figure 2: Semi-quantitative RT-PCR of BAT1 and DDXL mRNA in frontal cortex of AD (n = 12) and control cases (n = 16). Data is represented as Box-plots showing median values and quartiles. (A) BAT1 mRNA levels normalized against β-ACTIN (Mann-Whitney U test: *P = .037), (B) BAT1 mRNA levels normalized against GAPDH (Mann-Whitney U test: **P = .057).

Mentions: In order to test whether transcription of BAT1 and the homologous gene DDXL was altered in AD, mRNA levels of both BAT1 and DDXL were examined in brain frontal cortex tissue of AD and control cases. Analysis of BAT1 mRNA levels (Figure 2) revealed significantly elevated mRNA levels for BAT1 normalized against β-ACTIN (a) while normalization with GAPDH (b) showed marginal significance for increased BAT1 mRNA levels in the AD brains (Mann-Whitney U test: P = .037 and P = .057 respectively).


Association of alleles carried at TNFA -850 and BAT1 -22 with Alzheimer's disease.

Gnjec A, D'Costa KJ, Laws SM, Hedley R, Balakrishnan K, Taddei K, Martins G, Paton A, Verdile G, Gandy SE, Broe GA, Brooks WS, Bennett H, Piguet O, Price P, Miklossy J, Hallmayer J, McGeer PL, Martins RN - J Neuroinflammation (2008)

Semi-quantitative RT-PCR of BAT1 and DDXL mRNA in frontal cortex of AD (n = 12) and control cases (n = 16). Data is represented as Box-plots showing median values and quartiles. (A) BAT1 mRNA levels normalized against β-ACTIN (Mann-Whitney U test: *P = .037), (B) BAT1 mRNA levels normalized against GAPDH (Mann-Whitney U test: **P = .057).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2538517&req=5

Figure 2: Semi-quantitative RT-PCR of BAT1 and DDXL mRNA in frontal cortex of AD (n = 12) and control cases (n = 16). Data is represented as Box-plots showing median values and quartiles. (A) BAT1 mRNA levels normalized against β-ACTIN (Mann-Whitney U test: *P = .037), (B) BAT1 mRNA levels normalized against GAPDH (Mann-Whitney U test: **P = .057).
Mentions: In order to test whether transcription of BAT1 and the homologous gene DDXL was altered in AD, mRNA levels of both BAT1 and DDXL were examined in brain frontal cortex tissue of AD and control cases. Analysis of BAT1 mRNA levels (Figure 2) revealed significantly elevated mRNA levels for BAT1 normalized against β-ACTIN (a) while normalization with GAPDH (b) showed marginal significance for increased BAT1 mRNA levels in the AD brains (Mann-Whitney U test: P = .037 and P = .057 respectively).

Bottom Line: These cytokines are encoded by genes representing several interleukins and TNFA, which are associated with AD.The gene coding for HLA-B associated transcript 1 (BAT1) lies adjacent to TNFA in the central major histocompatibility complex (MHC).BAT1, a member of the DEAD-box family of RNA helicases, appears to regulate the production of inflammatory cytokines associated with AD pathology.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre of Excellence for Alzheimer's Disease Research and Care, Faculty of Computing, Health and Science, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, 6027, WA, Australia. agnjec@cyllene.uwa.edu.au

ABSTRACT

Background: Inflammatory changes are a prominent feature of brains affected by Alzheimer's disease (AD). Activated glial cells release inflammatory cytokines which modulate the neurodegenerative process. These cytokines are encoded by genes representing several interleukins and TNFA, which are associated with AD. The gene coding for HLA-B associated transcript 1 (BAT1) lies adjacent to TNFA in the central major histocompatibility complex (MHC). BAT1, a member of the DEAD-box family of RNA helicases, appears to regulate the production of inflammatory cytokines associated with AD pathology. In the current study TNFA and BAT1 promoter polymorphisms were analysed in AD and control cases and BAT1 mRNA levels were investigated in brain tissue from AD and control cases.

Methods: Genotyping was performed for polymorphisms at positions -850 and -308 in the proximal promoter of TNFA and position -22 in the promoter of BAT1. These were investigated singly or in haplotypic association in a cohort of Australian AD patients with AD stratified on the basis of their APOE epsilon4 genotype. Semi-quantitative RT-PCR was also performed for BAT1 from RNA isolated from brain tissue from AD and control cases.

Results: APOE epsilon4 was associated with an independent increase in risk for AD in individuals with TNFA -850*2, while carriage of BAT1 -22*2 reduced the risk for AD, independent of APOE epsilon4 genotype. Semi-quantitative mRNA analysis in human brain tissue showed elevated levels of BAT1 mRNA in frontal cortex of AD cases.

Conclusion: These findings lend support to the application of TNFA and BAT1 polymorphisms in early diagnosis or risk assessment strategies for AD and suggest a potential role for BAT1 in the regulation of inflammatory reactions in AD pathology.

Show MeSH
Related in: MedlinePlus