Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Glycogen synthase kinase-3β 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 John, Broe, G. Anthony, Tang, Nelson, Lam, Linda, Powell, John F., Lovestone, Simon and Schofield, Peter R. 2008. Glycogen synthase kinase-3β and tau genes interact in Alzheimer's disease. Annals of Neurology 64 (4) , pp. 446-454. 10.1002/ana.21476

Full text not available from this repository.


Objective We examined the epistatic effect between haplotypes of glycogen synthase kinase-3β (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. β-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 β-catenin levels compared with a control vector (p < 0.001). Conversely, cotransfection of both of these molecules increased β-catenin signaling. Interpretation Our genetic and biochemical analyses have identified a novel interaction between Tau and GSK-3β 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 β-catenin levels and pathogenicity.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Publisher: Wiley-Liss Inc
ISSN: 0364-5134
Last Modified: 04 Jun 2017 03:31

Citation Data

Cited 54 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item