ABSTRACT
Alzheimer's disease (AD) is a complex neurodegenerative disorder and the most common type of dementia in the elderly. Although its cause is not completely known, several studies suggest that oxidative stress plays an important role in the etiology of this disease. The SIRT1 and SOD2 proteins are linked to pathways that may impair oxidative stress. In this study, we analyzed the association between polymorphisms in these genes and in the APOE gene, through RT-PCR, as well as between environmental factors and the risk of AD. Additionally, the thiobarbituric acid reactive substance assay was performed to estimate the plasma level of malondialdehyde (MDA), a biomarker of lipid peroxidation. Furthermore, some cytogenetic studies indicate that cells of AD patients show increased chromosomal damage; thus, we performed the micronucleus cytome assay to assess cytogenetic damage in AD patients. As expected, the APOE polymorphisms were found to be highly associated with AD. Additionally, the CT genotype of the SIRT1 gene showed a positive association with the disease. The frequencies of genomic damage (micronucleus, buds, nucleoplasmic bridges and binucleated cells), the presence of cell death biomarkers (condensed chromatin, karyorrhexis and pyknosis), and the plasma level of MDA were significantly greater in AD patients than in controls. Our results support the hypothesis that AD is a condition with increased oxidative stress and genomic instability, which may contribute to the neurodegeneration in AD.
Subject(s)
Alzheimer Disease , Aged , Alzheimer Disease/genetics , Humans , Lipid Peroxidation , Malondialdehyde , Oxidative Stress/genetics , Sirtuin 1/geneticsABSTRACT
Late-onset Alzheimer's disease (LOAD) is a multifactorial neurodegenerative disorder that corresponds to most Alzheimer's disease (AD) cases. Inflammation is frequently related to AD, whereas microglial cells are the major phagocytes in the brain and mediate the removal of Aß peptides. Microglial cell dsyregulation might contribute to the formation of amyloid plaques, a hallmark of AD. Genome-wide association studies have reported genetic loci associated with the inflammatory pathway involved in AD. Among them, rs3865444 CD33, rs3764650 ABCA7, rs6656401 CR1, and rs610932 MS4A6A variants in microglial genes are associated with LOAD. These variants are proposed to participate in the clearance of Aß peptides. However, their association with LOAD was not validated in all case-control studies. Thus, the present work aimed to assess the involvement of CD33 (rs3865444), ABCA7 (rs3764650), CR1 (rs6656401), and MS4A6A (rs610932) with LOAD in a sample from southeastern Brazil. The genotype frequencies were assessed in 79 AD patients and 145 healthy elders matched for sex and age. We found that rs3865444 CD33 acts as a protective factor against LOAD. These results support a role for the inflammatory pathway in LOAD.
Subject(s)
ATP-Binding Cassette Transporters/genetics , Alzheimer Disease/genetics , Membrane Proteins/genetics , Polymorphism, Single Nucleotide , Receptors, Complement 3b/genetics , Sialic Acid Binding Ig-like Lectin 3/genetics , Aged , Aged, 80 and over , Brazil , Case-Control Studies , Female , Gene Frequency , Humans , Male , Microglia/metabolismABSTRACT
Genome-wide association study (GWAS) has identified several novel genes associated with the risk of Alzheimer's disease (AD), which is a progressive neurodegenerative disease in elders. However, most of the novel genes have not been validated through replication in separated populations. Among them, the BIN1 gene is involved in endocytosis and intracellular trafficking as well as in the formation of ß amyloid plaques and neurofibrillary tangles, which are the main pathological hallmarks of AD. The IL-6 gene has also been frequently associated with AD; however, consistent results have not been found. IL-6, a cytokine from the immune system, is implicated in the pathogenesis of several degenerative diseases. Similar to BIN1, it is suggested that IL-6 is also involved in the formation of ß amyloid plaques. In this case-control study, we aimed to investigate whether single nucleotide polymorphisms in the BIN1 (rs744373) and IL-6 (rs1800795) genes are associated with AD. Genotype frequencies were evaluated via PCR-RFLP in 82 late-onset AD patients and 159 elderly healthy controls, who were matched by age and gender. In this study, no association was found for either polymorphism, suggesting that these genes are not implicated in the aetiology of AD in all populations.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Alzheimer Disease/genetics , Interleukin-6/genetics , Nuclear Proteins/genetics , Tumor Suppressor Proteins/genetics , Aged , Aged, 80 and over , Case-Control Studies , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Male , Polymorphism, Single Nucleotide , Risk FactorsABSTRACT
Alzheimer's disease (AD) is a complex neurodegenerative disorder and the primary cause of dementia in the elderly and causes a decrease in cognition, functionality, and behaviour. Genetic risk factors play an important role in the pathogenesis of AD. In this case-control study, we aimed to investigate whether single nucleotide polymorphisms in MTHFR (rs1801133), PICALM (3851719), CLU (rs11136000), and CR1 (rs6701713) are associated with AD. Genotype frequencies were evaluated in 82 late-onset AD patients and 161 elderly healthy controls matched by age and gender. We detected a significant association of the MTHFR rs1801133 and PICALM rs3851179 polymorphisms with AD. The results of this study support the hypothesis that several genes are involved in the aetiology of AD.
Subject(s)
Alzheimer Disease/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Monomeric Clathrin Assembly Proteins/genetics , Polymorphism, Single Nucleotide , Aged , Aged, 80 and over , Alleles , Case-Control Studies , Female , Genotype , Humans , Male , Odds RatioABSTRACT
Ipriflavone (7-isopropoxy-isoflavone) is a semisynthetic isoflavone derivative from daidzein and prescribed to prevent and treat osteoporosis in postmenopausal women. In the present study, ipriflavone was investigated with regard to their cytotoxic and mutagenic effects using the micronucleus assay (MN) in vivo on cells of bone marrow and peripheral blood of Swiss albino mice and the micronucleus test with the cytokinesis-blocked micronucleus assay (CBMN assay) on human peripheral blood lymphocytes. The studies were performed in mice with three dosages of the drug, 1.71, 8.57 and 42.85 mg/kg bw in single oral exposure, and for two dosages, 5 and 10 µg/mL in the CBMN assay. Ipriflavone, in the dosages tested, did not differ from controls neither in the induction of MN nor induced cytotoxicity to cells in the in vivo test. However, in the CBMN assay, the concentration of 10 µg/mL induced a statistically significant increase in MN formation and decreased cell proliferation, demonstrating to be mutagenic and cytotoxic at this concentration.
