beta-Amyloid (Abeta), 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, Abeta 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 Abeta. The combination of
cerebral ischemia and Abeta 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 Abeta treatment alone or the combination of
ischemia and Abeta. High K(+)-evoked increase in ACh release had a tendency to be inhibited by either
ischemia or Abeta treatment alone and was significantly inhibited by the combination of both. Moreover, combination of
ischemia and Abeta induced apoptosis of pyramidal neurons in the CA1 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 Abeta. 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.