Pharmacological studies in the animal model for Alzheimer' s disease with life-style related disease

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The amyloid cascade hypothesis of Alzheimer disease (AD) pathogenesis postulates that β-amyloid peptide (Aβ ) accumulation in critical brain regions was reported to contribute to memory impairment. In the present study, firstly, to elucidate the importance of structural and functional roles of Aβ, we investigated the degree of memory disturbances and hippocampal ACh release using oligomeric form of Aβ. Oligomeric Aβ injected in the brain of the rat which was subjected 10min cerebral ischemia caused significant memory disturbance in 8-arm radial maze task. The degree of the memory disturbances induced by oligomeric Aβ was rather strong than that induced by aggregated Aβ we previously reported. A microdialysis study showed that spontaneous release of acetylcholine (ACh) from dorsal hippocampus tended to decrease in oligomeric Aβ injected rats. The high potassium-evoked increase of hippocampal ACh release strongly decreased by oligomeric Aβ. We previously demonstrated aggregated A β induced apoptosis of CA1 cells of the hippocampus. But oligomeric A R did not induce apoptosis. In the next experiment, to classify the effect of diabetes mellitus on the memory disturbances in Aβ treated rats. Oligomeric AB injected to the diabetic Goto-Kakizaki (GK) rats showed the elevated glucose level and insulin resistance. The swimming time until the rats reached to the platform in Morris water maze task was increased in AB treated GK rats. These findings suggest that oligomeric form of Aβ may strongly affect the neurotransmitter mechanism by its neurotoxicity without showing cellular apoptosis. We represented the influence of life-style related disease such as cerebrovascular disease or diabetes mellitus affect the symptoms of AD using the animal models. These models may be useful for developing new drugs for AD.