RESUMEN
Alzheimer's disease (AD) is characterized by progressive decline in memory and other cognitive domains, accompanied by early loss of presynaptic terminals, amyloid-bearing neuritic plaques and neurofibrillary tangles containing hyperphosphorylated tau. The mechanisms leading to neurodegeneration are not completely understood, however, recent evidence suggests that alterations in p59Fyn kinase, an Src family tyrosine kinase, might contribute to AD pathogenesis. In this context, the main objective of the present study was to investigate the relationship between Fyn protein levels and the neurological and neuropathological alterations in AD. We found, by quantitative immunoblotting, that in AD, Fyn levels were increased in the insoluble fraction and decreased in the soluble fraction. Soluble Fyn levels were directly correlated with the cognitive scores and levels of synaptophysin immunoreactivity, and inversely correlated with neurofibrillary tangle counts in the frontal cortex. Consistent with these findings, the immunocytochemical analysis showed that in AD cases, Fyn levels were decreased in the synapses and increased in the neuronal cell bodies where it was colocalized with neurofibrillary tangles. Taken together, these findings suggest that alterations in Fyn localization might be associated with neurofibrillary pathology and synapse loss in AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Regulación de la Expresión Génica , Proteínas Proto-Oncogénicas/metabolismo , Familia-src Quinasas/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Western Blotting/métodos , Encéfalo/metabolismo , Encéfalo/patología , Química Encefálica/fisiología , Progresión de la Enfermedad , Humanos , Inmunohistoquímica/métodos , Modelos Lineales , Escala del Estado Mental/estadística & datos numéricos , Proteínas del Tejido Nervioso/metabolismo , Ovillos Neurofibrilares/metabolismo , Cambios Post Mortem , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-fyn , Estadísticas no Paramétricas , Fracciones Subcelulares/metabolismo , Sinaptofisina/metabolismo , Familia-src Quinasas/genética , Proteínas tauRESUMEN
This study investigated the influence of age at onset on cognitive performance, neuropathological and neurochemical features in autopsy-confirmed sporadic Lewy body variant (LBV) and in Alzheimer's disease (AD). We compared 28 early-onset (< or = 70 years) LBV subjects with 28 matched late-onset (> 70 years) subjects. Similarly, we examined the same features in 89 early onset AD and 89 matched late onset AD patients. Patients with early onset LBV and early onset AD declined more rapidly, had more neuritic plaques, and greater neocortical cholinergic loss compared to late onset LBV and late onset AD subjects. Taken together, these results suggest that for both LBV and AD, earlier age at onset may predict a more aggressive disease course.