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

阿尔茨海默病（AD）发病机制的淀粉样蛋白级联假说假定β-淀粉样蛋白肽（Aβ）在关键脑区的积累被报道有助于记忆障碍。在本研究中，首先，为了阐明Aβ的结构和功能作用的重要性，我们使用寡聚体形式的Aβ来研究记忆障碍的程度和海马ACh的释放。脑缺血10 min后，脑内注射寡聚Aβ可引起大鼠在八臂迷宫中的记忆障碍。寡聚体Aβ引起的记忆障碍程度比我们以前报道的聚集体Aβ引起的记忆障碍程度更强。微透析研究表明，寡聚Aβ注射大鼠背侧海马乙酰胆碱（ACh）的自发释放有减少的趋势。寡聚体Aβ可显著降低高钾诱发的海马ACh释放增加。我们以前证明聚集的A β诱导海马CA 1细胞凋亡。但寡聚体AR不诱导细胞凋亡。在接下来的实验中，分类糖尿病对Aβ治疗大鼠记忆障碍的影响。给糖尿病Goto-Kakizaki（GK）大鼠注射寡聚AB后，血糖升高，胰岛素抵抗。在Morris水迷宫实验中，AB组大鼠到达平台的游泳时间明显延长。这些结果表明，寡聚体形式的Aβ可能通过其神经毒性强烈影响神经递质机制，而不显示细胞凋亡。本研究通过动物模型研究了生活方式相关疾病如脑血管病、糖尿病等对AD症状的影响。这些模型可能有助于开发新的AD药物。

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.