RESUMO
Alterations in cell-matrix 'contact' are often related to a disruption of cell cycle regulation and, as such, occur variously in neoplasia. Given the recent findings showing cell cycle alterations in Alzheimer disease, we undertook a study of ADAM-1 and 2 (A Disintegrin And Metalloprotease), developmentally-regulated, integrin-binding, membrane-bound metalloproteases. Our results show that whereas ADAM-1 and 2 are found in susceptible hippocampal neurons in Alzheimer disease, these proteins were not generally increased in similar neuronal populations in younger or age-matched controls except in association with age-related neurofibrillary alterations. This increase in both ADAM-1 and 2 in cases of Alzheimer disease was verified by immunoblot analysis (P < 0.05). An ADAM-induced loss of matrix integration would effectively "reset" the mitotic clock and thereby stimulate re-entry into the cell cycle in neurons in Alzheimer disease. Furthermore, given the importance of integrins in maintaining short-term memory, alterations in ADAM proteins or their proteolytic activity could also play a proximal role in the clinico-pathological manifestations of Alzheimer disease.
Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Matriz Extracelular/metabolismo , Glicoproteínas de Membrana/metabolismo , Metaloendopeptidases/metabolismo , Proteínas ADAM , Idoso , Idoso de 80 Anos ou mais , Fertilinas , Humanos , Immunoblotting , Imuno-Histoquímica , Pessoa de Meia-IdadeRESUMO
Recent reports have established oxidative stress and damage as playing a role in the pathogenesis of a number of neurodegenerative diseases including Alzheimer disease, Parkinson disease, corticobasal degeneration, Pick's disease and Alexander's disease. Here we present evidence that oxidative damage is also one of the earliest cytopathological markers of neuronal dysfunction in frontotemporal dementia.
Assuntos
Demência/metabolismo , Lobo Frontal/metabolismo , Estresse Oxidativo/fisiologia , Lobo Temporal/metabolismo , Biomarcadores , Demência/patologia , Lobo Frontal/patologia , Humanos , Lobo Temporal/patologiaRESUMO
Hippocampal and select cortical neuronal populations in Alzheimer's disease exhibit phenotypic changes characteristic of cells re-entering the cell division cycle. Therefore, in this study, we investigated whether components, known to trigger cellular proliferation and differentiation, upstream of the ras/mitogen-activated kinase pathway, could contribute to the activation of a signal transduction cascade in Alzheimer's disease. We found that proteins implicated in signal transduction from cell surface receptors via the ras pathway, namely Grb2 and SOS-1, were altered in cases of Alzheimer's disease in comparison to age-matched controls. SOS is increased in susceptible pyramidal neurons, while Grb2 shows more subtle alterations in subcellular distribution. Importantly, both SOS-1 and Grb2 show considerable overlap with early cytoskeletal abnormalities suggesting that the alteration in signal transduction molecules is a concurrent, if not preceding, event in the pathogenesis of Alzheimer's disease. Taken together with the cell cycle abnormalities previously reported, these findings suggest that a signal derived from the cell surface contributes to a stimulus for neurons in Alzheimer's disease to re-enter the cell cycle.