RESUMEN
The original recognition of the paired helical filaments is discussed and amplified. The original description of what are now the neuropil threads is mentioned. The ensuing importance of both these structures is emphasised and a morphology-based hypothesis of the development of the disease from the original stimuli is offered.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , Encéfalo/patología , Hilos del Neurópilo/metabolismo , Enfermedad de Alzheimer/genética , Humanos , Neuritas/metabolismo , Neuritas/patología , Hilos del Neurópilo/genéticaRESUMEN
The total amount of hyperphosphorylated tau protein (p-tau load), present as neurofibrillary tangles (NFTs), neuropil threads or plaque neurites, was quantified in the frontal cortex of 109 cases of sporadic Alzheimer's disease (AD) and 35 cases of familial AD due to missense mutations in the presenilin-1, presenilin-2 and amyloid precursor protein genes. p-tau load was inversely correlated with age at onset of illness in both sporadic and familial AD but not with duration of disease. There was no difference in p-tau load between cases of familial AD and others with sporadic AD, matching the familial cases for apolipoprotein E (APO E) genotype. However, p-tau was greater in cases of familial and sporadic AD in the presence of APO E epsilon4 allele and increased with gene dose. Conversely, p-tau load tended to be lower when epsilon2 allele was present. In sporadic AD, tau load was highly significantly correlated with amyloid beta40 (Abeta40), but not Abeta42(43), load. These data indicate that the burden of pathological tau deposited in the brain in both familial and sporadic AD is favoured in the presence of APO E epsilon4 allele and also related to the amount of Abeta40, this also being higher when epsilon4 allele is present. Abeta40 plaques are rich in microglial cells and it is possible that p-tau pathology in AD is triggered by reaction of microglial cells to the presence of Abeta40 and not this peptide directly.
Asunto(s)
Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Encéfalo/patología , Proteínas tau/metabolismo , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Femenino , Genotipo , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Ovillos Neurofibrilares/genética , Ovillos Neurofibrilares/patología , Hilos del Neurópilo/genética , Hilos del Neurópilo/patología , Placa Amiloide/genética , Placa Amiloide/patología , Proteínas tau/genéticaAsunto(s)
Alelos , Enfermedad de Alzheimer/patología , Apolipoproteínas E/genética , Encéfalo/patología , Demencia/patología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Demencia/genética , Demencia/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Inmunohistoquímica , Masculino , Ovillos Neurofibrilares/genética , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Hilos del Neurópilo/genética , Hilos del Neurópilo/metabolismo , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patología , Reacción en Cadena de la Polimerasa , Proteínas tau/metabolismoRESUMEN
We have studied biochemical and structural parameters of several missense and deletion mutants of tau protein (G272V, N279K, DeltaK280, P301L, V337M, R406W) found in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). The mutant proteins were expressed on the basis of both full-length tau (htau40) and constructs derived from the repeat domain. They were analyzed with respect to the capacity to enhance microtubule assembly, binding of tau to microtubules, secondary structure content, and aggregation into Alzheimer-like paired helical or straight filaments. We find that the mutations cause a moderate decrease in microtubule interactions and stabilization, and they show no gross structural changes compared with the natively unfolded conformation of the wild-type protein, but the aggregation into PHFs is strongly enhanced, particularly for the mutants DeltaK280 and P301L. This gain of pathological aggregation would be consistent with the autosomal dominant nature of the disease.