title: Hippocampal damage and cytoskeletal disruption resulting from impaired energy metabolism. Implications for Alzheimer disease.
abstract: To determine if impaired energy metabolism might contribute to some aspects of Alzheimer disease (AD), including the vulnerability of the CA1 region of the hippocampal formation and the altered cytoskeleton evident in neurofibrillary tangles, we examined the effects of metabolic poisons on neuronal damage and cytoskeletal disruption in the hippocampal formation. Intrahippocampal injection of 3-nitropropionic acid (3-NP) and malonic acid resulted in neuronal death, particularly in CA1. Cytoskeletal disruption included loss of dendritic MAP2, but sparing of axonal gamma. MK-801 (a noncompetitive NMDA receptor antagonist) did not atentuate the lesions produced by intrahippocampal injection of malonate. MK-801, however, was effective against intrastriatal malonate. Acute systemic 3-NP resulted in neuronal damage and cytoskeletal disruption in the CA1 region of the hippocampal formation, including an extensive loss of MAP2 immuno-reactivity, but sparing of gamma. The neuronal loss in CA1 was delayed as compared to striatum. Chronic intraventricular infusion of 3-NP produced a different pattern of neuronal damage. Loss of gamma-1 immuno-reactivity was observed in CA3 and CA1 s. orients, whereas MAP2 immunostaining was preserved. These results demonstrate that chronic and acute administration of metabolic inhibitors produce distinct patterns of neuronal damage and cytoskeletal disruption. The results further suggest a differential involvement of the NMDA receptor in malonate-induced neuronal damage in striatum as compared to the hippocampus. The pattern of neuronal damage and cytoskeletal disruption observed following acute metabolic impairment resembled some aspects of neurofibrillary pathology in AD, but did not result in gamma hyperphosphorylation.
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington 40536, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Geddes
authors.forename: Z
authors.initials: Z
authors.lastname: Pang
authors.forename: D H
authors.initials: DH
authors.lastname: Wiley
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001369:Axons / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004734:Energy Metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D008314:Malonates / Q000633:toxicity; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D017378:Quinolinic Acid / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008314:Malonates; D008869:Microtubule-Associated Proteins; D016291:Dizocilpine Maleate; C030290:malonic acid; D017378:Quinolinic Acid