Co-injection of β-amyloid with ibotenic acid induces synergistic loss of rat hippocampal neurons

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. (C) 1998 IBRO. Published by Elsevier Science Ltd.