A Study of the Impact of Death Receptor 4 (DR4) Gene Polymorphisms in Alzheimer’s Disease

Abstract

Background: Excessive apoptosis is believed to play a role in many degenerative and non-degenerative neurological diseases including Alzheimer's disease (AD). Much recent data suggest that apoptotic mechanisms may represent the missing link between Aβ deposition and proteolysis of tau protein.However, there is emerging evidence that apoptotic mechanisms may play a role in Alzheimer's Disease pathogenesis in the absence of overt apoptosis. TNF-related apoptosis inducing ligand receptor 1 (Death Receptor 4, DR4) might impair the apoptotic signal transduction and lead to dysregulation of the homeostasis between cell survival and cell death.Aims: The aim of our study was to further investigate the relationship between genetic variants of DR4 and Alzheimer's Disease.Study Design: Case control study.Methods: Sixty-eight patients with AD were included in the study. The control group comprised 72 subjects without signs of neurodegenerative diseases, as evidenced by the examination.DNA was extracted from whole blood using the salting-out procedure. Genotypes were identified by restriction fragment length polymorphism analysis of polymerase chain reaction (PCR-RFLP) products. Results:We observed significant differences in the genotypic distribution of the rs6557634 polymorphism in AD patients compared with controls (p<0.05); our data suggest that the GA genotype in rs6557634 could be protective against AD (p<0.05). However, there were no significant differences between AD patients and control groups in terms of the DR4 rs20575 polymorphism (p>0.05) and the DR4 rs20576 polymorphism (p>0.05). According to haplotype analysis of the DR4 gene for rs6557634, rs20575 and rs20576 polymorphisms, GCA and GCC haplotypes might be a risk factor for AD. Also, we have shown that ACA, GGC and GGA haplotypes might be protective factors against AD. Conclusion:The present results indicate for the first time the possible contribution of the DR4 gene rs6557634, rs20575, rs20576 polymorphisms in Alzheimer's Disease, which may influence susceptibility to Alzheimer's Disease.

The Role of DNA Methylation and Histone Modifications in Neurodegenerative Diseases: A Systematic Review

“…Furthermore, genes of proteins such as death receptor 4 (DR4) and NF-ĸB are involved in processes that may play a role in the pathogenesis of AD such as apopotosis and/or inflammation. DR4 and NF-ĸB genes were reported to be differentially methylated in AD cases [104, 105]. DR4 might impair the apoptotic signal transduction and may cause apoptosis of brain cells[104].…”

“…DR4 and NF-ĸB genes were reported to be differentially methylated in AD cases [104, 105]. DR4 might impair the apoptotic signal transduction and may cause apoptosis of brain cells[104]. Polymorphisms of the DR4 gene have been shown to influence susceptibility to AD [104].…”

“…DR4 might impair the apoptotic signal transduction and may cause apoptosis of brain cells[104]. Polymorphisms of the DR4 gene have been shown to influence susceptibility to AD [104]. NF-ĸB activation is a common feature of many neurodegenerative diseases, particularly of AD [105].…”