Cerebral ischemia combined with beta-amyloid impairs spatial memory in the eight-arm radial maze task in rats

Abstract

beta-Amyloid (A beta), a major component of senile plaques in Alzheimer's disease, has been implicated in neuronal cell death, a characteristic feature of this condition. In our previous experiments using primary cultures of hippocampal neurons, A beta treatment induced neuronal cell death, displaying morphological characteristics of apoptosis that was significantly enhanced by hypoxia. Based on these results, we developed a simple in vivo rat model of Alzheimer's disease using cerebral ischemia, instead of hypoxia, combined with continuous intracerebroventricular administration of A beta. The combination of cerebral ischemia and A beta administration, but not either treatment alone, significantly impaired spatial memory in an eight-arm radial maze. A microdialysis study showed that spontaneous release of acetylcholine (ACh) from the dorsal hippocampus had a tendency to decrease in response to A beta treatment alone or the combination of ischemia and A beta. High K+-evoked increase in ACh release had a tendency to be inhibited by either ischemia or A beta treatment alone and was significantly inhibited by the combination of both. Moreover, combination of ischemia and A beta induced apoptosis of pyramidal neurons in the CAI region of the hippocampus. Donepezil, a drug currently in clinical use for Alzheimer's disease, improved the impairment of spatial memory induced by cerebral ischemia combined with A beta. These findings suggest that ischemia is an important factor facilitating the symptoms of Alzheimer's disease, and this model may be useful for developing new drugs for the treatment of Alzheimer's disease. (c) 2006 Published by Elsevier B.V.