title: beta-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.
abstract: Senile plaques composed mainly by beta-amyloid (Abeta) protein are one of the pathological hallmarks of Alzheimer's disease (AD). In vitro, Abeta 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 Abeta 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 Abeta. We have studied Abeta 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 Abeta peptide toxicity occurs, probably resulting from decreased glucose metabolism and mitochondrial ATP production. Synaptosomal response to energy impairment and Abeta toxicity was evaluated by the MTT assay. Results suggest that synapses may be particularly sensitive to metabolic perturbation, which in turn exacerbates Abeta 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.
authors.affiliation: Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México.
authors.forename: Clorinda
authors.initials: C
authors.lastname: Arias
authors.forename: Teresa
authors.initials: T
authors.lastname: Montiel
authors.forename: Ricardo
authors.initials: R
authors.lastname: Quiroz-Báez
authors.forename: Lourdes
authors.initials: L
authors.lastname: Massieu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D007274:Injections, Intraperitoneal; D007461:Iodoacetates / Q000494:pharmacology; D008297:Male; D008845:Microinjections; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D019579:Neocortex / Q000737:chemistry / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D009574:Nitro Compounds; D010446:Peptide Fragments / Q000008:administration & dosage / Q000633:toxicity*; D017729:Presynaptic Terminals / Q000737:chemistry / Q000187:drug effects*; D011422:Propionates / Q000494:pharmacology; D019289:Pyruvic Acid / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000737:chemistry / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007461:Iodoacetates; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D010446:Peptide Fragments; D011422:Propionates; C074636:amyloid beta-protein (25-35); D016291:Dizocilpine Maleate; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D005947:Glucose; C015392:3-nitropropionic acid