RESUMEN
The pathogenesis of Alzheimer's disease (AD) is only partially understood. ß-amyloid (Aß) is physiologically generated by sequential cleavage of its precursor protein by the ß- and the γ-secretase and it is normally disposed of. In Alzheimer's disease, Aß is excessively produced or less dismissed, but the hypothesis on its physiological and pathological role are heterogeneous and often discordant. It has been described a positive feedback loop from the γ- to the ß-secretase cleavages of Aß precursor protein, which is activated by mutations of Presenilin 1 (PS1), the catalytic core of the γ-secretase. These findings show that Aß precursor protein as well the activity of the γ-secretase are required to obtain the up-regulation of ß-secretase which is induced by Presenilin 1 mutations. Then, Aß 1-42 is the Aß precursor protein derivative that up-regulates the expression of ß-secretase, and c-jun N-terminal kinase (JNK)/c-Jun and ERK1/2 are involved. Here, we describe the activation of ß-secretase and c-jun N-terminal kinase related proteins by monomeric Aß 1-42, defining the conditions that most efficiently strike the described signaling without producing toxicity. Taken together these data imply that monomeric Aß 1-42, at non-toxic concentrations and time frames, are able to induce a signaling pathway that leads to transcriptional activation of ß-secretase.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/farmacología , Ácido Aspártico Endopeptidasas/metabolismo , Fragmentos de Péptidos/farmacología , Regulación hacia Arriba/efectos de los fármacos , Secretasas de la Proteína Precursora del Amiloide/genética , Análisis de Varianza , Ácido Aspártico Endopeptidasas/genética , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , MAP Quinasa Quinasa 4/metabolismo , Microscopía Electrónica de Transmisión , Neuroblastoma/patología , Interferencia de ARN/fisiología , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Sales de Tetrazolio , Tiazoles , Transfección/métodosRESUMEN
OBJECTIVE: To develop a blood-based test for screening populations at risk for Alzheimer disease. DESIGN: Case-control study. Subjects A total of 180 patients with mild cognitive impairment (MCI) and 105 age-matched, cognitively normal controls. INTERVENTIONS: The titer of beta-amyloid 1-42 autoantibodies in the plasma was obtained at the time of diagnosis and evaluated by enzyme-linked immunosorbent assay before and after dissociation of the antigen-antibody complexes. A total of 107 patients with MCI were followed up for 36 months; 70 of the 107 cases progressed to Alzheimer disease. RESULTS: The average level of beta-amyloid 1-42 plasma autoantibodies in patients with MCI that progressed to Alzheimer disease, but not that of the stable cases, was significantly higher than in cognitively normal controls (P < .001). CONCLUSIONS: The results suggest that the plasma beta-amyloid 1-42 autoantibodies parallel beta-amyloid 42 deposition in the brain, which is known to precede by several years the clinical onset of Alzheimer disease. The evaluation of beta-amyloid 1-42 autoantibodies after dissociation of the complexes is a simple and inexpensive method that can be used to predict the occurrence of Alzheimer disease.
Asunto(s)
Péptidos beta-Amiloides/inmunología , Trastornos del Conocimiento/sangre , Trastornos del Conocimiento/inmunología , Inmunoglobulina G/sangre , Fragmentos de Péptidos/inmunología , Amnesia/sangre , Amnesia/complicaciones , Apolipoproteína E4/genética , Estudios de Casos y Controles , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/genética , Estudios de Seguimiento , Humanos , ProbabilidadRESUMEN
Mild cognitive impairment is often considered a transitional condition prodromal to Alzheimer's disease. The dissection of genetic risk factors predisposing to mild cognitive impairment is paramount to assess the individual predisposition and reliably evaluate the effectiveness of early therapeutic interventions. We designed a cross-sectional analysis to test whether the occurrence of mild cognitive impairment is influenced by variations of the tau protein gene. The genotypes of seven polymorphisms tagging the major tau haplotypes were assayed on 186 patients with amnestic mild cognitive impairment and 191 unrelated controls. Association study was conducted by logistic regression including APOE genotype and age as covariates. Case-control analysis showed that the common H1 haplotype is significantly overrepresented in patients (OR, 95% CI: 2.31, 1.52-3.51; p<0.001), whereas did not provide positive signals for any of the H1 sub-haplotypes that had been described as associated with Alzheimer inverted exclamation mark s disease. This finding was confirmed when the epsilon4 allele of the APOE gene was taken into account (OR, 95% CI: 2.319, 1.492-3.603; p<0.001). These results firstly suggest that the risk of mild cognitive impairment is influenced by tau protein gene variations and that mild cognitive impairment shares a common genetic background with Alzheimer's disease. They may help elucidating the genetic risk to cognitive decline and designing effective clinical trials.
Asunto(s)
Enfermedad de Alzheimer/genética , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/genética , Haplotipos/genética , Proteínas tau/genética , Anciano , Alelos , Apolipoproteínas E/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Polimorfismo Genético/genética , Índice de Severidad de la EnfermedadRESUMEN
Amnestic mild cognitive impairment (aMCI) is considered a prodromal stage of Alzheimer's disease (AD). We measured plasma levels of amyloid-beta40 (Abeta40) and Abeta42 in 191 subjects with aMCI. Seventy-nine of them were clinically followed for two years. In the total cohort of aMCI cases, the average level of Abeta42, as well as the Abeta42/Abeta40 ratio, was significantly higher than those of the 102 cognitively normal age-matched subjects. The aMCI cases that converted to probable AD within 2 years had higher levels of Abeta42 and, to a lesser extent, Abeta40 than the stable cases. However the large variability of measured values indicates that plasma Abeta is not a suitable marker of incipient AD.