title: Co-injection of beta-amyloid with ibotenic acid induces synergistic loss of rat hippocampal neurons.
abstract: Senile plaques are a pathological hallmark of Alzheimer's disease. The major component of senile plaques is beta-amyloid which consists of approximately 4000 mol. wt of peptide. Accumulating evidence suggests that beta-amyloid may represent the underlying cause of Alzheimer's disease. In vitro, beta-amyloid has been shown either to be directly neurotoxic or to potentiate neurotoxic effects of excitatory amino acids. However, beta-amyloid toxicity in vivo has not always been reproducible. In this study, we injected beta-amyloid fragment 1-40 or 25-35 alone or in combination with a small amount of ibotenic acid, an excitatory amino acid, into rat hippocampus, and examined the histological and immunohistochemical changes two weeks after injection. Although beta-amyloid alone or ibotenic acid alone exerted only minimal degenerating effects on neurons just around the injection site, the co-injection of beta-amyloid 1-40 or beta-amyloid 25-35 with ibotenic acid produced drastic neuronal loss; the haematoxylin-eosin staining revealed that most neurons not only around the injection site but also in distant areas including CA1, CA4 and dentate gyrus were depleted. The neuronal loss occurred in a dose-dependent manner with respect to ibotenic acid. Immunohistochemical analysis showed that beta-amyloid with ibotenic acid induced great depletion of microtubule-associated protein-2 immunoreactivity and infiltration of astrocytes and microglia on neuronal loss. In addition, some apoptotic neuronal death indicated by DNA fragmentation and nucleic condensation was observed. Beta-amyloid depositions detected by two different types of anti-human beta-amyloid antibodies were limited to the injection site. Dizocilpine maleate (MK-801), an antagonist for an excitatory amino acid receptor, completely inhibited the neuronal death in rat hippocampus. These results suggest that the co-injection of beta-amyloid with a small amount of ibotenic acid provides a useful model for investigation of the pathogenetic mechanisms leading to Alzheimer's disease.
authors.affiliation: Neuroscience Research Laboratories, Sankyo Co. Ltd, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Morimoto
authors.forename: K
authors.initials: K
authors.lastname: Yoshimi
authors.forename: T
authors.initials: T
authors.lastname: Tonohiro
authors.forename: N
authors.initials: N
authors.lastname: Yamada
authors.forename: T
authors.initials: T
authors.lastname: Oda
authors.forename: I
authors.initials: I
authors.lastname: Kaneko
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis; D004357:Drug Synergism; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D007051:Ibotenic Acid / Q000633:toxicity*; D007150:Immunohistochemistry; D008297:Male; D008869:Microtubule-Associated Proteins / Q000032:analysis; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D009498:Neurotoxins; D010446:Peptide Fragments / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D008869:Microtubule-Associated Proteins; D009498:Neurotoxins; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D007051:Ibotenic Acid