RESUMO
Elevated cerebral levels of amyloid beta-protein (Abeta) occur in Alzheimer's disease (AD), yet only a few patients show evidence of increased Abeta production. This observation suggests that many, perhaps most, cases of AD are caused by faulty clearance of Abeta. Megalin, which plays an important role in mediating Abeta clearance, is an attractive candidate gene for genetic association with AD. To investigate this hypothesis, we analyzed the megalin gene in a population of 2,183 subjects. Genetic analysis indicated that the rs3755166 (G/A) polymorphism located in the megalin promoter associated with risk for AD, dependently of apolipoprotein E genotype. The rs3755166 AA genotype frequency was significantly greater in AD patients than in control subjects. Furthermore, the luciferase reporter assay indicated that the rs3755166 A variant has 20% less transcriptional activity than the rs3755166 G variant. This study provides strong evidence that this megalin polymorphism confers a greater risk for AD, and supports a biological role for megalin in the neurodegenerative processes involved in AD.
Assuntos
Doença de Alzheimer/genética , Polimorfismo Genético , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/imunologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/imunologia , Apolipoproteínas E/genética , Apolipoproteínas E/imunologia , Estudos de Casos e Controles , Feminino , Genes , Genótipo , Humanos , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/imunologia , Masculino , Estudos Multicêntricos como Assunto , Sequências Reguladoras de Ácido Nucleico , Fatores de RiscoRESUMO
Mutations of presenilin 1 (PSEN1) are associated with monogenic Alzheimer's disease (AD); polymorphisms at this gene may therefore be associated with the sporadic form of the disease. In fact, recent meta-analyses and whole-genome association studies indicate PSEN1 as one of the few genes significantly associated with AD risk. Several polymorphisms have been analyzed in PSEN1. The present work examined the possible modulation of the risk of AD by a PSEN1 polymorphism (dbSNP rs3025786) located in intron 7, which we found during a denaturing gradient gel electrophoresis mutation screening of the gene, and which was previously reported as 'suspected' in the public databases. The study of a Spanish case-control sample of 1,183 individuals showed this polymorphism to be associated with AD in an apolipoprotein E (APOE)-specific manner: more specifically, to carry the PSEN1 C allele was associated with a decreased AD risk among carriers of the APOE4 allele. Thus, the present results reinforce the possible involvement of PSEN1 in sporadic AD.
Assuntos
Doença de Alzheimer/genética , Apolipoproteína E4/genética , Presenilina-1/genética , Idoso , Alelos , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/psicologia , Sondas de DNA , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , Polimorfismo Genético/genética , Escalas de Graduação Psiquiátrica , Espanha/epidemiologiaRESUMO
Alzheimer's disease (AD) is a complex multifactorial disorder involving a number of genetic and environmental factors, with severe head injury consistently reported as a major non-genetic risk factor. The adrenergic activation that occurs during major trauma increases cAMP levels, therefore the cAMP signaling pathway might be involved in AD pathogenesis. Time course of candidate gene expression following adrenergic stimulation with isoproterenol was assayed in neuroblastoma cells by quantitative reverse transcription (RT)-PCR. Then, genetic association studies of polymorphisms in several of these candidate genes were performed. Association studies in two independent case-control samples showed a polymorphism in DSC1, encoding desmocollin 1--a member of the desmosomal cadherins--which modulated AD susceptibility in a gender-specific manner. These results are in accordance with the potential involvement of the adrenergic signaling pathway in AD pathogenesis.
Assuntos
Agonistas Adrenérgicos beta/farmacologia , Doença de Alzheimer/genética , Desmocolinas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Isoproterenol/farmacologia , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Feminino , Regulação da Expressão Gênica/fisiologia , Frequência do Gene , Genótipo , Humanos , Modelos Logísticos , Masculino , Neuroblastoma , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Fatores Sexuais , Fatores de TempoRESUMO
INTRODUCTION: Mild cognitive impairment (MCI) is a cognitive disturbance in which intensity is not enough to be classified as dementia and does not affect significantly the functioning or activities of daily living. The MCI has a progression rate to Alzheimer-type dementia (ATD) related to different factors. AIM: To evaluate the association between the presence of psychological and behavioural symptoms (PBS) with progression to ATD en MCI subjects. PATIENTS AND METHODS: We evaluated 318 patients with MCI assessed in a Dementia Unit of Catalonia between 1998 to 2002 who were followed five years after the MCI diagnosis. We determined the PBS presence, those classified as affective, behavioural and psychotic symptoms. We also assessed sociodemographic aspects and the ApoE genotype. RESULTS: The mean age was 74 +/- 7.87 years-old, 56.7% presented PBS, with affective (53%), behavioural (32.2%) and psychotic symptoms (14.8%). In the study, 32.1% progressed to ATD. We found association between the presence of PBS and the progression to ATD (OR = 2.77; 95% CI = 1.66-4.63), specifically with behavioural and psychotic symptoms. The ApoE epsilon4 allele showed association with the progression to ATD (OR = 1.81; 95% CI = 1.11-2.94). The logistic regression model showed a significant association between the PBS and the epsilon4 allele with the progression to ATD. CONCLUSIONS: The PBS presence in MCI patients is associated with ATD progression with or without ApoE epsilon4 allele.