β-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

• Published in: Experimental neurology Vol. 176; no. 1; pp. 163 - 174
• Main Authors: Arias, Clorinda, Montiel, Teresa, Quiroz-Báez, Ricardo, Massieu, Lourdes
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.07.2002; Elsevier
• Subjects: Adenosine Triphosphate - metabolism; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - administration & dosage; Amyloid beta-Peptides - toxicity; Animals; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Dizocilpine Maleate - pharmacology; Energy Metabolism - drug effects; Enzyme Inhibitors - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; excitotoxicity; Glucose - metabolism; Glycolysis - drug effects; glycolysis inhibition; Hippocampus - chemistry; Hippocampus - drug effects; Hippocampus - pathology; Injections, Intraperitoneal; Iodoacetates - pharmacology; Male; Medical sciences; Microinjections; Mitochondria - chemistry; Mitochondria - drug effects; Mitochondria - metabolism; mitochondrial failure; Neocortex - chemistry; Neocortex - drug effects; neurodegeneration; Neurology; Neuroprotective Agents - pharmacology; Nitro Compounds; Peptide Fragments - administration & dosage; Peptide Fragments - toxicity; Presynaptic Terminals - chemistry; Presynaptic Terminals - drug effects; Propionates - pharmacology; Pyruvic Acid - pharmacology; Rats; Rats, Wistar; synaptic toxicity; Synaptosomes - chemistry; Synaptosomes - drug effects; β-amyloid; mitochondrial failure; glycolysis inhibition; neurodegeneration; excitotoxicity; Alzheimer's disease; synaptic toxicity; β-amyloid; Nervous system diseases; Energy metabolism; Rat; Alzheimer disease; Toxicity; Rodentia; Glucose; Cerebral disorder; In vivo; Vertebrata; Dentate gyrus; Mammalia; β Amyloid protein; Animal; Central nervous system disease; Degenerative disease; Hippocampus; Presynaptic
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1006/exnr.2002.7912

Senile plaques composed mainly by β-amyloid (Aβ) protein are one of the pathological hallmarks of Alzheimer's disease (AD). In vitro, Aβ 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 Aβ 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 Aβ. We have studied Aβ 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 Aβ peptide toxicity occurs, probably resulting from decreased glucose metabolism and mitochondrial ATP production. Synaptosomal response to energy impairment and Aβ toxicity was evaluated by the MTT assay. Results suggest that synapses may be particularly sensitive to metabolic perturbation, which in turn exacerbates Aβ 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.