RESUMO
Tau protein and amyloid s (Abeta), two major components of neuropathology in Alzheimer disease (AD), have been applied for establishment of more useful biomarkers and therapeutic approaches. Total tau protein in CSF is a biomarker for AD, however increased levels of total tau in CSF were also observed in other neurological disease with dementia. Phosphorylation is an important feature of tau protein and phosphorylated tau in CSF is useful to distinguish AD from other disease. Abeta has toxic effects on neuronal cells, and its mechanisms are complicated. One of mechanism of Abeta-cytotoxicity is a down-regulation of XIAP, and this effect is observed in the low concentration of Abeta. XIAP might be a therapeutic target employing compounds that increase expression of XIAP in neuronal cells.
Assuntos
Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/toxicidade , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/fisiologia , Proteínas tau/líquido cefalorraquidiano , Doença de Alzheimer/etiologia , Biomarcadores , Humanos , Fosforilação , Proteínas tau/metabolismoRESUMO
Epidemiological studies have shown that elevated plasma homocysteine (Hcy) levels play an important role in the pathogenesis of Alzheimer's disease (AD). In spite of the evidence that a C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene elevates plasma Hcy levels, the impact of the C677T polymorphism on the development of AD is controversial. Here, we performed a genetic case-control study in a Japanese population to investigate whether three polymorphisms of the MTHFR gene, C677T (Ala222Val), A1298C (Glu429Ala), and A1793G (Arg594Gln), are associated with the development of late-onset AD (LOAD). In our study, the MTHFR gene had four major regional haplotypes: Haplotype A (677C-1298A-1793G), Haplotype B (677T-1298A-1793G), Haplotype C (677C-1298C-1793G), and Haplotype D (677C-1298C-1793A). The frequency of Haplotype C in LOAD was significantly lower than that in control group. Furthermore, the benefit conferred by the presence of at least one Haplotype C was stronger in LOAD patients who lacked the ApoE 4 allele (OR=0.293; 95% CI=0.115-0.744; P=0.010). The results indicate that Haplotype C of the MTHFR gene is protective against the development of LOAD.
Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/genética , Encéfalo/enzimologia , Haplótipos/genética , Imunidade Inata/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Idoso , Doença de Alzheimer/epidemiologia , Apolipoproteína E4 , Apolipoproteínas E/sangue , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Frequência do Gene , Predisposição Genética para Doença/genética , Testes Genéticos , Homocisteína/biossíntese , Homocisteína/sangue , Humanos , Japão/epidemiologia , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Polimorfismo Genético/genéticaRESUMO
Recent epidemiological studies have emphasized the impact of elevated blood homocysteine levels on the pathogenesis of Alzheimer's disease (AD). In spite of a significant impact of a MTHFR C677T polymorphism on the blood homocysteine levels, the association between the C677T polymorphism and AD remains controversial. Therefore, other unidentified genetic factor(s) that regulate blood homocysteine levels may exist. Here, we have analyzed the 5'-upstream region of the MTHFR gene and examined AD patients (n = 223) and nondemented individuals (n = 323) for polymorphisms in the 5'-upstream region of the MTHFR gene. We identified two polymorphisms (-713G/A and -393C/A, upstream of the start codon). We found no significant relationship between AD and the 5'-upstream region polymorphisms of the MTHFR gene. Thus, our study does not reinforce the hypothesis of an independent involvement of the MTHFR gene upstream region polymorphisms in AD risk.