Common Polymorphisms in the GSK3 β Gene May Contribute to the Pathogenesis of Alzheimer Disease

Abstract

Objective:

Although it is well known that GSK3β participates in the proliferation and survival of various tumor cells, its role in diseases of the central nervous system has been sparsely documented. In the past few years, studies regarding the relationship between GSK3β rs334558 T>C and rs6438552 C>T polymorphisms and Alzheimer disease (AD) risk have yielded contradictory results. As such, this meta-analysis seeks to satisfy the need to further investigate this relationship.

Methods:

In this research, published studies regarding the association of GSK3β rs6438552 and rs334558 mutation with AD risk was systematically assessed. Studies were retrieved from MEDLINE, Science Citation Index, the Cochrane Library, PubMed, Embase, CINAHL, Current Contents Index, Chinese Biomedical, Chinese Journal Full-Text, and Weipu Journal. Pooled odds ratios and 95% confidence intervals were calculated for allele contrast and homozygous, heterozygous, dominant, and recessive genetic model comparisons.

Results:

It was found that GSK3β rs334558 T>C and rs6438552 C>T polymorphisms were correlated with susceptibility to AD under 4 genetic models (all P < .05). In country-stratified subgroups, the results showed increased risk of developing AD in rs334558 T>C polymorphism among Chinese and Spain populations in majority groups. GSK3β rs6438552 C>T polymorphism was correlated with increased the risk of developing AD only in Australian populations.

Conclusion:

Our findings suggest that there exists a significant association between GSK3β rs334558 T>C polymorphism and increased susceptibility of AD. Moreover, future updated studies with stratified case–control population are warranted for validation studies.

Keywords

genetic polymorphism Alzheimer disease meta-analysis

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References

Roychaudhuri

Yang

Hoshi

Teplow

. Amyloid beta-protein assembly and Alzheimer disease. J Biol Chem. 2009;284 (8):4749–4753.

Salloway

Sperling

Gilman

. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73 (24):2061–2070.

Bertram

Lill

Tanzi

. The genetics of Alzheimer disease: back to the future. Neuron. 2010;68(2):270–281.

Frisoni

Fox

Jack

Jr Scheltens

Thompson

. The clinical use of structural MRI in Alzheimer disease. Nat Rev Neurol. 2010;6(2):67–77.

Bai

Shi

Yuan

. Association of a GSK-3beta polymorphism with brain resting-state function in amnestic-type mild cognitive impairment. J Alzheimers Dis. 2012;32(2):387–396.

Izzo

Forlenza

Santos

. Single-nucleotide polymorphisms of GSK3B, GAB2 and SORL1 in late-onset Alzheimer's disease: interactions with the APOE genotype. Clinics (Sao Paulo). 2013;68(2):277–280.

Garcia-Gorostiaga

Sanchez-Juan

Mateo

. Glycogen synthase kinase-3 beta and tau genes interact in Parkinson's and Alzheimer's diseases. Ann Neurol. 2009;65(6):759–761; author reply 761-752.

Scarmeas

Luchsinger

Schupf

. Physical activity, diet, and risk of Alzheimer disease. JAMA. 2009;302(6):627–637.

Ciobica

Padurariu

Bild

Stefanescu

. Cardiovascular risk factors as potential markers for mild cognitive impairment and Alzheimer's disease. Psychiatr Danub. 2011;23 (4):340–346.

10.

Sereno

Coma

Rodriguez

. A novel GSK-3beta inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo. Neurobiol Dis. 2009;35 (3):359–367.

11.

Song

Teng

Cai

Tang

. Activation of Akt/GSK-3beta signaling pathway is involved in intermedin(1–53) protection against myocardial apoptosis induced by ischemia/reperfusion. Apoptosis. 2009;14 (11):1299–1307.

12.

Zhang

Koenig

Harrison

. Mutant K-Ras increases GSK-3beta gene expression via an ETS-p300 transcriptional complex in pancreatic cancer. Oncogene. 2011;30 (34):3705–3715.

13.

Leng

Liang

Ren

Marinova

Leeds

Chuang

. Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: roles of glycogen synthase kinase-3 inhibition. J Neurosci. 2008;28(10):2576–2588.

14.

Mateo

Infante

Llorca

Rodriguez

Berciano

Combarros

. Association between glycogen synthase kinase-3beta genetic polymorphism and late-onset Alzheimer's disease. Dement Geriatr Cogn Disord. 2006;21(4):228–232.

15.

Chatterjee

Sang

Lawless

Jackson

. Dissociation of tau toxicity and phosphorylation: role of GSK-3beta, MARK and Cdk5 in a Drosophila model. Hum Mol Genet. 2009;18(1):164–177.

16.

Zhang

Yang

Zhang

Tan

. Association analysis of GSK3B and MAPT polymorphisms with Alzheimer's disease in Han Chinese. Brain Res. 2011;1391:147–153.

17.

Kalinderi

Fidani

Katsarou

Clarimon

Bostantjopoulou

Kotsis

. GSK3beta polymorphisms, MAPT H1 haplotype and Parkinson's disease in a Greek cohort. Neurobiol Aging. 2011;32(3):546. e541–e545.

18.

Mateo

Vazquez-Higuera

Sanchez-Juan

. Epistasis between tau phosphorylation regulating genes (CDK5R1 and GSK-3beta) and Alzheimer's disease risk. Acta Neurol Scand. 2009;120(2):130–133.

19.

Kwok

Loy

Hamilton

. Glycogen synthase kinase-3beta and tau genes interact in Alzheimer's disease. Ann Neurol. 2008;64(4):446–454.

20.

Wang

Qin

Wei

Zuo

Jia

. [Association of the polymorphism in promoter region of GSK3B with Alzheimer's disease in Chinese Han population]. J Neurosci Ment Health. 2013;13(4):331–334.

21.

McKhann

Drachman

Folstein

Katzman

Price

Stadlan

. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984;34(7):939–944.

22.

Sperber

Leight

Goedert

Lee

. Glycogen synthase kinase-3 beta phosphorylates tau protein at multiple sites in intact cells. Neurosci Lett. 1995;197(2):149–153.

23.

Zintzaras

Ioannidis

. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol. 2005;28(2):123–137.

24.

Higgins

Thompson

. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–1558.

25.

Song

Gilbody

. Bias in meta-analysis detected by a simple, graphical test. Increase in studies of publication bias coincided with increasing use of meta-analysis. BMJ. 1998;316(7129):471.

26.

Russ

Lovestone

Powell

. Identification of sequence variants and analysis of the role of the glycogen synthase kinase 3 beta gene and promoter in late onset Alzheimer's disease. Mol Psychiatry. 2001;6(3):320–324.

27.

Reddy

. Amyloid beta-induced glycogen synthase kinase 3beta phosphorylated VDAC1 in Alzheimer's disease: implications for synaptic dysfunction and neuronal damage. Biochim Biophys Acta. 2013;1832(12):1913–1921.

28.

Jope

Yuskaitis

Beurel

. Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochem Res. 2007;32(4-5):577–595.

29.

Duka

Joyce

Sidhu

. Alpha-synuclein contributes to GSK-3beta-catalyzed tau phosphorylation in Parkinson's disease models. FASEB J. 2009;23 (9):2820–2830.

30.

Zhang

Tao

Liang

. Secalonic acid D induced leukemia cell apoptosis and cell cycle arrest of G(1) with involvement of GSK-3beta/beta-catenin/c-Myc pathway. Cell Cycle. 2009;8(15):2444–2450.