Glycogen synthase kinase-3beta and tau genes interact in Alzheimer's disease

John B. J. Kwok, Clement T. Loy, Gillian Hamilton, Edmond Lau, Marianne Hallupp, Julie Williams, Michael J. Owen, G. Anthony Broe, Nelson Tang, Linda Lam, John F. Powell, Simon Lovestone, Peter R. Schofield

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: We examined the epistatic effect between haplotypes of glycogen synthase kinase-3beta (GSK3B) gene and microtubule-associated protein Tau (MAPT) gene in Alzheimer's disease (AD). METHODS: A genetic association study of three AD cohorts was made. Linear regression analyses were used to examine effects of MAPT polymorphisms on gene expression and alternative splicing. beta-Catenin levels and signaling were determined using Western blot and luciferase reporter assays in cells transfected with a combination of GSK3B and MAPT complementary DNA. RESULTS: Consistent interaction between GSK3B and MAPT genes in three late-onset AD cohorts was observed, with the GSK3B haplotype (T-T) significantly increasing the risk for AD in individuals with at least one H2 haplotype (odds ratio, 1.68-2.33; p = 0.005-0.036). The GSK3B haplotype was significantly protective in the Chinese cohort (odds ratio, 0.33; p = 0.016), after adjusting for the effect of age and sex. There are significant differences in in vivo transcriptional efficiency between the two MAPT haplotypes (H1 and H2) as determined by measurement of cerebellar transcripts (p <0.001). Overexpression of either MAPT or GSK3B resulted in decreased beta-catenin levels compared with a control vector (p <0.001). Conversely, cotransfection of both of these molecules increased beta-catenin signaling. INTERPRETATION: Our genetic and biochemical analyses have identified a novel interaction between Tau and GSK-3beta in late-onset AD causative factors. Our data are consistent with an epistatic model of interaction where discordant levels of GSK3B and MAPT gene expression can lead to altered beta-catenin levels and pathogenicity.
Original languageEnglish
Pages (from-to)446-454
Number of pages9
JournalAnnals of neurology
Volume64
Issue number4
DOIs
Publication statusPublished - Oct 2008

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Glycogen Synthase Kinases
Microtubule-Associated Proteins
Alzheimer Disease
Haplotypes
beta Catenin
Genes
Odds Ratio
Gene Expression
Alternative Splicing
Genetic Association Studies
Luciferases
Virulence
Molecular Biology
Linear Models
Complementary DNA
Western Blotting
Regression Analysis

Keywords

  • Alzheimer's disease
  • glycogen synthase kinase-3ß
  • microtubule-associated protein Tau
  • GSK3B
  • MAPT

Cite this

Kwok, J. B. J., Loy, C. T., Hamilton, G., Lau, E., Hallupp, M., Williams, J., ... Schofield, P. R. (2008). Glycogen synthase kinase-3beta and tau genes interact in Alzheimer's disease. Annals of neurology, 64(4), 446-454. https://doi.org/10.1002/ana.21476
Kwok, John B. J. ; Loy, Clement T. ; Hamilton, Gillian ; Lau, Edmond ; Hallupp, Marianne ; Williams, Julie ; Owen, Michael J. ; Broe, G. Anthony ; Tang, Nelson ; Lam, Linda ; Powell, John F. ; Lovestone, Simon ; Schofield, Peter R. / Glycogen synthase kinase-3beta and tau genes interact in Alzheimer's disease. In: Annals of neurology. 2008 ; Vol. 64, No. 4. pp. 446-454.
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Kwok, JBJ, Loy, CT, Hamilton, G, Lau, E, Hallupp, M, Williams, J, Owen, MJ, Broe, GA, Tang, N, Lam, L, Powell, JF, Lovestone, S & Schofield, PR 2008, 'Glycogen synthase kinase-3beta and tau genes interact in Alzheimer's disease', Annals of neurology, vol. 64, no. 4, pp. 446-454. https://doi.org/10.1002/ana.21476

Glycogen synthase kinase-3beta and tau genes interact in Alzheimer's disease. / Kwok, John B. J.; Loy, Clement T.; Hamilton, Gillian; Lau, Edmond ; Hallupp, Marianne; Williams, Julie; Owen, Michael J.; Broe, G. Anthony; Tang, Nelson; Lam, Linda; Powell, John F.; Lovestone, Simon; Schofield, Peter R.

In: Annals of neurology, Vol. 64, No. 4, 10.2008, p. 446-454.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Glycogen synthase kinase-3beta and tau genes interact in Alzheimer's disease

AU - Kwok, John B. J.

AU - Loy, Clement T.

AU - Hamilton, Gillian

AU - Lau, Edmond

AU - Hallupp, Marianne

AU - Williams, Julie

AU - Owen, Michael J.

AU - Broe, G. Anthony

AU - Tang, Nelson

AU - Lam, Linda

AU - Powell, John F.

AU - Lovestone, Simon

AU - Schofield, Peter R.

PY - 2008/10

Y1 - 2008/10

N2 - OBJECTIVE: We examined the epistatic effect between haplotypes of glycogen synthase kinase-3beta (GSK3B) gene and microtubule-associated protein Tau (MAPT) gene in Alzheimer's disease (AD). METHODS: A genetic association study of three AD cohorts was made. Linear regression analyses were used to examine effects of MAPT polymorphisms on gene expression and alternative splicing. beta-Catenin levels and signaling were determined using Western blot and luciferase reporter assays in cells transfected with a combination of GSK3B and MAPT complementary DNA. RESULTS: Consistent interaction between GSK3B and MAPT genes in three late-onset AD cohorts was observed, with the GSK3B haplotype (T-T) significantly increasing the risk for AD in individuals with at least one H2 haplotype (odds ratio, 1.68-2.33; p = 0.005-0.036). The GSK3B haplotype was significantly protective in the Chinese cohort (odds ratio, 0.33; p = 0.016), after adjusting for the effect of age and sex. There are significant differences in in vivo transcriptional efficiency between the two MAPT haplotypes (H1 and H2) as determined by measurement of cerebellar transcripts (p <0.001). Overexpression of either MAPT or GSK3B resulted in decreased beta-catenin levels compared with a control vector (p <0.001). Conversely, cotransfection of both of these molecules increased beta-catenin signaling. INTERPRETATION: Our genetic and biochemical analyses have identified a novel interaction between Tau and GSK-3beta in late-onset AD causative factors. Our data are consistent with an epistatic model of interaction where discordant levels of GSK3B and MAPT gene expression can lead to altered beta-catenin levels and pathogenicity.

AB - OBJECTIVE: We examined the epistatic effect between haplotypes of glycogen synthase kinase-3beta (GSK3B) gene and microtubule-associated protein Tau (MAPT) gene in Alzheimer's disease (AD). METHODS: A genetic association study of three AD cohorts was made. Linear regression analyses were used to examine effects of MAPT polymorphisms on gene expression and alternative splicing. beta-Catenin levels and signaling were determined using Western blot and luciferase reporter assays in cells transfected with a combination of GSK3B and MAPT complementary DNA. RESULTS: Consistent interaction between GSK3B and MAPT genes in three late-onset AD cohorts was observed, with the GSK3B haplotype (T-T) significantly increasing the risk for AD in individuals with at least one H2 haplotype (odds ratio, 1.68-2.33; p = 0.005-0.036). The GSK3B haplotype was significantly protective in the Chinese cohort (odds ratio, 0.33; p = 0.016), after adjusting for the effect of age and sex. There are significant differences in in vivo transcriptional efficiency between the two MAPT haplotypes (H1 and H2) as determined by measurement of cerebellar transcripts (p <0.001). Overexpression of either MAPT or GSK3B resulted in decreased beta-catenin levels compared with a control vector (p <0.001). Conversely, cotransfection of both of these molecules increased beta-catenin signaling. INTERPRETATION: Our genetic and biochemical analyses have identified a novel interaction between Tau and GSK-3beta in late-onset AD causative factors. Our data are consistent with an epistatic model of interaction where discordant levels of GSK3B and MAPT gene expression can lead to altered beta-catenin levels and pathogenicity.

KW - Alzheimer's disease

KW - glycogen synthase kinase-3ß

KW - microtubule-associated protein Tau

KW - GSK3B

KW - MAPT

U2 - 10.1002/ana.21476

DO - 10.1002/ana.21476

M3 - Article

VL - 64

SP - 446

EP - 454

JO - Annals of neurology

JF - Annals of neurology

SN - 0364-5134

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ER -