ß-amyloid neurotoxicity is exacerbated during glycolysis inhibition and mitochondrial impairment in the rat hippocampus in vivo and in isolated nerve terminals: Implications for alzheimer's disease
Por:
Arias C., Montiel T., Quiroz-Báez R., Massieu L.
Publicada:
1 ene 2002
Resumen:
Senile plaques composed mainly by ?-amyloid (A?) protein are one of the pathological hallmarks of Alzheimer's disease (AD). In vitro, A? and its active fragment 25-35 have been shown either to be directly neurotoxic or to exacerbate the damaging effect of other neurotoxic insults. However, the attempts to replicate A? neurotoxicity in vivo have yielded conflicting results. One of the most consistent alterations in AD is a reduced resting glucose utilization. Important evidence suggests that impairment of brain energy metabolism can lead to neuronal damage or facilitate the deleterious effects of some neurotoxic agents. In the present study we have investigated the influence of glycolysis inhibition induced by iodoacetate, and mitochondrial impairment induced by 3-nitropropionic acid (3-NP), in the toxicity of A?. We have studied A? neurotoxicity during energy deficiency both in vivo in the dentate gyrus of the hippocampal formation and in presynaptic terminals isolated from neocortex and hippocampus. Results show that during metabolic inhibition an enhanced vulnerability of hippocampal neurons to A? peptide toxicity occurs, probably resulting from decreased glucose metabolism and mitochondrial ATP production. Synaptosomal response to energy impairment and A? toxicity was evaluated by the MTT assay. Results suggest that synapses may be particularly sensitive to metabolic perturbation, which in turn exacerbates A? toxicity. The present data provide experimental support to the hypothesis that certain risk factors such as metabolic dysfunction and amyloid accumulation may interact to exacerbate AD, and that metabolic substrates such as pyruvate may play a role as a therapeutic tool. © 2002 Elsevier Science (USA).
Filiaciones:
Arias C.:
Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Instituto de Fisiología Celular, Mexico
Montiel T.:
Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico
Quiroz-Báez R.:
Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Instituto de Fisiología Celular, Mexico
Massieu L.:
Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico
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