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  • Original Research Article
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Identification of sequence variants and analysis of the role of the glycogen synthase kinase 3 β gene and promoter in late onset Alzheimer's disease

Molecular Psychiatry volume 6, pages 320–324 (2001)Cite this article

Abstract

alzheimer's disease (ad) is a disorder characterised by a progressive deterioration in memory and other cognitive functions. glycogen synthase kinase 3 beta (gsk3β) phosphorylates the microtubule associated protein tau at sites that are aberrantly phosphorylated in ad. gsk3β binds to presenilin 1 and plays a role in wnt and insulin signalling cascades, both of which have been proposed to be linked to ad. moreover gsk3β activity may be altered in ad brain. these observations suggest a central role for gsk3β in ad and led us to investigate gsk3β as a candidate gene for ad. we sought to identify sequence variations in the gene and its promoter, as these could have an effect on activity and expression leading to abnormal function. sequencing over 3000 bp of the gsk3β putative promoter revealed there to be five sequence variations, two of which were common (>10%). However on further examination none of these, either alone or in synergy, had any association with late onset AD. Stratification of the data by APOE ε4 status also produced no significant association. Sequencing of the GSK3β coding region revealed no variations. This would suggest that the aberrant phosphorylation of tau by GSK3β in AD is not due to sequence variations in the gene or its promoter.

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Acknowledgements

This study was supported by the Wellcome Trust (049542/Z). The authors wish to thank Dr Clive Holmes for the use of the clinical and genotypic data for the Camberwell Dementia Case Register. Samples from participants in the MRC trial of assessment and management of elderly people in the community (MRC Elderly Study) were collected in collaboration with the trial investigators: Professor Astrid Fletcher, London School of Hygiene & Tropical Medicine (Principal investigator), and co-investigators Dr Dee Jones, University of Wales College of Medicine and Professor Chris Bulpitt, Imperial College. We also thank Drs Kwok-Fai Lau and Pang-Chui Shaw for the GSK3β promoter sequence, the London MRC brain bank for providing tissue, Drs Maria J Arranz and Ammar Al-Chalabi for their statistical knowledge and Aaron Jeffries for his Unix skills.

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  1. Department of Neuroscience, Institute of Psychiatry, London, SE5 8AF, UK

    C Russ, S Lovestone & J F Powell

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  1. C Russ
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Correspondence to J F Powell.

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Russ, C., Lovestone, S. & Powell, J. Identification of sequence variants and analysis of the role of the glycogen synthase kinase 3 β gene and promoter in late onset Alzheimer's disease. Mol Psychiatry 6, 320–324 (2001). https://doi.org/10.1038/sj.mp.4000852

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