Elsevier

Neuroscience Letters

Volume 391, Issue 3, 2 January 2006, Pages 147-149
Neuroscience Letters

Effect of the functional toll-like receptor 4 Asp299Gly polymorphism on susceptibility to late-onset Alzheimer's disease

https://doi.org/10.1016/j.neulet.2005.08.047Get rights and content

Abstract

Experimental data have shown an upregulated expression of toll-like receptors, particularly toll-like receptor 4 (TLR4), in neurodegeneration. The Asp299Gly polymorphism of the TLR4 gene has been associated with an attenuated receptor signalling and a blunted inflammatory response. In the present study, we sought to determine whether this common genetic variant could influence susceptibility to late-onset Alzheimer's disease (LOAD) in an Italian population sample. A cohort of 277 LOAD patients and 300 cognitively healthy controls were genotyped for the TLR4 Asp299Gly polymorphism using restriction isotyping. The frequency of the minor 299Gly allele was significantly higher in the controls than in the LOAD cases (7.2% versus 3.1%, respectively, P = 0.003). Additionally, the frequency of the variant genotypes (Asp/Gly and Gly/Gly) was 13.0% in the controls and 5.4% in LOAD patients (P = 0.002). After adjustment for age, gender, and the APOE ɛ4 carrier status, the odds ratio for the development of LOAD associated with the Asp/Gly and Gly/Gly versus Asp/Asp genotype was 0.37 (95% CI: 0.20–0.69, P = 0.002). Our data further support a role for innate immunity in neurodegeneration and give the first evidence that the TLR4 Asp299Gly variant may be protective toward the development of LOAD.

References (21)

  • J.E. Hixson et al.

    Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI

    J. Lipid Res.

    (1990)
  • A. Aderem et al.

    Toll-like receptors in the induction of the innate immune response

    Nature

    (2000)
  • D.M. Agnese et al.

    Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections

    J. Infect. Dis.

    (2002)
  • N. Ameziane et al.

    Association of the Toll-like receptor 4 gene Asp299Gly polymorphism with acute coronary events

    Arterioscler. Thromb. Vasc. Biol.

    (2003)
  • N.C. Arbour et al.

    TLR4 mutations are associated with endotoxin hyporesponsiveness in humans

    Nat. Genet.

    (2000)
  • C.R. Balistreri et al.

    Role of Toll-like receptor 4 in acute myocardial infarction and longevity

    JAMA

    (2004)
  • I. Blasko et al.

    Role of the immune system in the pathogenesis, prevention and treatment of Alzheimer's disease

    Drugs Aging

    (2003)
  • M. Bsibsi et al.

    Broad expression of Toll-like receptors in the human central nervous system

    J. Neuropathol. Exp. Neurol.

    (2002)
  • B. Draczynska-Lusiak et al.

    Oxidized lipoproteins may play a role in neuronal cell death in Alzheimer disease

    Mol. Chem. Neuropathol.

    (1998)
  • M. Folwaczny et al.

    Toll-like receptor (TLR) 2 and 4 mutations in periodontal disease

    Clin. Exp. Immunol.

    (2004)
There are more references available in the full text version of this article.

Cited by (0)

View full text