RESUMO
Several studies have attempted to confirm the association between the recently reported polymorphism located at position -491 in the transcriptional regulatory region of the Apolipoprotein E (ApoE) gene and Alzheimer's disease (AD). Results have been inconclusive, possibly due to the use of clinically diagnosed subjects and controls only. In this retrospective case-control study of 149 (96 AD and 53 controls) brain samples we show that homozygosity for the -491A variant is associated with an increased risk of development of AD. The genotype is also strongly associated with the presence of at least one epsilon4 allele (an established risk factor for AD) in women but not in men.
Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Mutação Puntual , Polimorfismo Genético , Apolipoproteína E4 , Encéfalo/metabolismo , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Análise de RegressãoRESUMO
BACKGROUND: Anticholinesterase therapies offer modest benefit to subgroups of AD sufferers. However, there has previously been no way of predicting which patients will respond to any of the drugs. OBJECTIVE: To discover if gender and/or apolipoprotein E genotype can be used as predictors of response in the clinical setting. DESIGN: 107 patients from the Bristol Memory Disorders Clinic took part in a double-blinded or open label trial of tacrine therapy for between 3 and 12 months or an open label trial of galanthamine therapy for 3 months. RESULTS: After 3 months of therapy, gender was found to be the only significant influence on the number of responders to anticholinesterase therapy. Men had a 73% greater chance of responding than women (p = 0.012). While ApoE genotype did not modify response to therapy in the short term, there are indications that it may affect response over the longer term (up to 12 months), and also that the initial advantage of male gender may not be maintained after 3 months. CONCLUSION: Gender is likely to be a more powerful determinant of outcome of anticholinesterase treatment than apolipoprotein E status in the short term.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Apolipoproteínas E/genética , Inibidores da Colinesterase/uso terapêutico , Doença de Alzheimer/genética , Método Duplo-Cego , Feminino , Galantamina/uso terapêutico , Genótipo , Humanos , Masculino , Caracteres Sexuais , Tacrina/uso terapêutico , Fatores de TempoAssuntos
Encéfalo , Neurologia , Psiquiatria , Bancos de Tecidos/organização & administração , Humanos , Pesquisa , Doadores de TecidosRESUMO
Apolipoprotein E (ApoE) is a potent risk factor for Alzheimer's disease. Since the loss of cholinergic function in Alzheimer's disease is known to occur at an early stage in the disease we have examined this function in normal subjects with an Apoepsilon4 allele to see if the deficit occurs in the absence of Alzheimer pathology or symptoms. We report that brain tissue obtained post-mortem from normal subjects and Alzheimer patients with an Apoepsilon4 allele has a lower cholinergic activity than tissue from those subjects without this allele. This has important significance for the interpretation of the cholinergic deficits found in Alzheimer's disease.
Assuntos
Doença de Alzheimer/enzimologia , Apolipoproteínas E/genética , Encéfalo/enzimologia , Colina O-Acetiltransferase/metabolismo , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/genética , Apolipoproteína E4 , Estudos de Casos e Controles , Genótipo , Hipocampo/enzimologia , Humanos , Pessoa de Meia-Idade , Lobo Occipital/enzimologia , Valores de Referência , Lobo Temporal/enzimologiaRESUMO
A truncated form of the human trkB gene has been cloned and sequenced. This gene is related to the trk family of tyrosine kinases, the products of which act as receptors for the neurotrophins. Of these, brain-derived neurotrophic factor and mammalian neurotrophin-4 are the known ligands for the TrkB receptor. Catalytic and non-catalytic (or truncated) forms of the trkB gene have been cloned for rat and mouse. In this study, using in situ hybridization, we describe the distribution of trkB messenger RNA in fetal and adult human brain.
Assuntos
Química Encefálica , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/análise , Receptor trkB/genética , Receptores de Fator de Crescimento Neural/genética , Sequência de Aminoácidos , Animais , Encéfalo/embriologia , Catálise , Clonagem Molecular , Sondas de DNA , DNA Complementar/genética , Hipocampo/química , Hipocampo/embriologia , Humanos , Hibridização in Situ Fluorescente , Camundongos , Dados de Sequência Molecular , Família Multigênica , Proteínas do Tecido Nervoso/análise , RNA Mensageiro/genética , Ratos , Receptores Proteína Tirosina Quinases/análise , Receptores Proteína Tirosina Quinases/genética , Receptor do Fator Neutrófico Ciliar , Receptor trkA/análise , Receptor trkA/genética , Receptor trkB/análise , Receptor trkC , Receptores de Fator de Crescimento Neural/análise , Homologia de Sequência de Aminoácidos , Especificidade da EspécieRESUMO
Nerve growth factor (beta-NGF) is known to have beneficial effects on cholinergic cell survival and to function both in vivo and in vitro. It has been speculated that this protein, or the lack of it, may be involved in the aetiology of Alzheimer's disease (AD). We describe the measurement of beta-NGF content in 4 regions of the cerebral cortex and the hippocampus in AD brain compared with brain tissue from age-matched normal subjects using a sensitive sandwich immunoassay (ELISA). There was no difference in beta-NGF content in any region examined in AD compared with normal values despite the marked loss of cortical cholinergic function.
Assuntos
Doença de Alzheimer/metabolismo , Córtex Cerebral/patologia , Colina O-Acetiltransferase/análise , Hipocampo/patologia , Fatores de Crescimento Neural/análise , Idoso , Doença de Alzheimer/patologia , Autopsia , Córtex Cerebral/enzimologia , Feminino , Hipocampo/enzimologia , Humanos , Masculino , Estudos Prospectivos , Valores de ReferênciaRESUMO
The binding characteristics of radiolabelled beta-nerve growth factor ([125I]NGF) have been determined on membrane preparations of basal forebrain from Alzheimer's disease (AD) brain and age-matched normal brains. [125I]NGF binds in a specific fashion indicative of a single receptor and is not displaced with microM concentrations of cytochrome c, insulin or epidermal growth factor (EGF). The mean dissociation constant (Kd) and the mean capacity (Bmax) of the NGF receptor were not significantly different between the 5 AD and 5 normal basal forebrain samples examined. Choline acetyltransferase (ChAT) activity was significantly reduced (P less than or equal to 0.001) in AD cerebral cortical samples compared with normal tissue.