Molecular pharmacological studies in the animal model for Alzheimer's disease

阿尔茨海默病动物模型的分子药理学研究

• 批准号: 13672407
• 负责人: IWASAKI Katsunori
• 金额: $ 2.24万
• 依托单位: Fukuoka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672407/
• 关键词: ALZHEIMER'S DISEASE; CEREBRAL ISCHEMIA; ChE-inhibitor; RAT; MAZE PERFORMANCE; MEMORY; ChE-阻害剤; β-アミロイド; 空間認知記憶; アポトーシス

β-Amyloid (Aβ) deposited in the senile plaques is thought to be a main cause of Alzheime's disease(AD). According to this AR hypothesis, we tried to develop new animal models of AD. (1) We found that human Tau transgenic mice (R406W) showed behavioral depression at the age of 10 months and SSRI inhibited this behavior. These facts suggested that serotonergic mechanism may play an important role at the early stage of AD. (2) Non-transgenic animal models of AD are also necessary for new drug development. Firstly, we developed a combination treatment of brief cerebral ischemia with intracerebral injection of Aβ1-42 in rats using 8-arm radial maze task. Neither Aβ1-42-treated nor ischemia-subjected rats showed the memory disturbances at the retention test of 7th day. On the other hand, the combination treatment of Aβ1-42 with 10 mm ischemia showed significant disruption of spatial memory Secondary, we combined the ovariectomy (OVX) and intracerebral injection of Aβ1-42 in female rats because of the fact that AD occurs with greater incidence in postmenopausal women. The combination treatment of Aβ1-42 with OVX also slowed significant decrease of serum estrogen and showed memory disturbance in 8-arm radial maze task. Further investigation of these two models indicated that Aβ-induced hippocampal apoptosis and ACh dysfunction may cause the AD's dementia and drugs inhibited these symptoms may be useful for the treatment of AD.

β-淀粉样蛋白（β-Amyloid，Aβ）沉积在老年斑中被认为是阿尔茨海默病（Alzheime 'sdisease，AD）的主要病因之一。根据这一AR假说，我们试图建立新的AD动物模型。(1)我们发现，人Tau转基因小鼠（R406 W）在10月龄时表现出行为抑郁，SSRI抑制了这种行为。这些事实表明，β-肾上腺素能机制可能在AD的早期阶段起重要作用。(2)AD的非转基因动物模型对于新药开发也是必要的。首先，我们采用八臂放射状迷宫实验建立了短暂脑缺血联合脑内注射Aβ1-42的治疗方法。Aβ1-42处理组和缺血组大鼠在第7天的记忆保持试验中均未出现记忆障碍。另一方面，Aβ1-42与10 mm缺血的联合治疗显示空间记忆的显著破坏。其次，我们在雌性大鼠中联合卵巢切除术（OVX）和脑内注射Aβ1-42，因为AD在绝经后女性中的发生率更高。Aβ1-42与OVX联合治疗也可延缓血清雌激素水平的显著下降，并在8臂迷宫中表现出记忆障碍。对这两种模型的进一步研究表明，Aβ诱导的海马细胞凋亡和ACh功能障碍可能导致AD的痴呆，抑制这些症状的药物可能有助于AD的治疗。

项目成果

James J.Palacino, M.Paul Murphy, Ohoshi Murayama, Katsunoii Iwasaki, Michihiro Fujiwara, Akihiko Takashima, Todd E.Golde, Benjamin Wolozin: "Presenilin 1 regulates β-catenin-mediated transcription in a glycogen synthase kinase-3-indipendent fashion"J.Biol

James J.Palacino、M.Paul Murphy、Ohoshi Murayama、Katsunoii Iwasaki、Michihiro Fujiwara、Akihiko Takashima、Todd E.Golde、Benjamin Wolozin：“Presenilin 1 以糖原合成酶激酶 3 独立的方式调节 β-catenin 介导的转录J·比奥尔

Yoshitaka Tatebayashi et al.: "Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau"Proceeding of National Academy of Sciences. vol.99,21. 13896-13901 (2002)

Yoshitaka Tatebayashi 等人：“表达突变体 (R406W) 人类 tau 的老年小鼠的 Tau 丝形成和联想记忆缺陷”《美国国家科学院院刊》。

James J.Palacino et al.: "Presenilin I regurates β-catenin-mediated transcription in a glycoge synthase kinase-3-indipendent fashion"Journal of Biological Chemistry. 276. 38563-38569 (2001)

James J. Palacino 等人：“Presenilin I 以独立于糖基合酶激酶 3 的方式调节 β-连环蛋白介导的转录”《生物化学杂志》276. 38563-38569 (2001)。

Katsunori Iwasaki et al.: "Ovariectomy combined with β amyloid impairs memory by decreasing acetylcholine release and α7nAChR expression without induction of apoptosis in the hippocampus CA1 neurons of rats"Neurotoxicity Research. 6(in press). (2004)

Katsunori Iwasaki 等人：“卵巢切除术联合 β 淀粉样蛋白通过减少乙酰胆碱释放和 α7nAChR 表达而损害记忆，而不诱导大鼠海马 CA1 神经元细胞凋亡”神经毒性研究 6（出版中）。

Yoshitaka Tatebayashi, Tomohiro Miyasaka, De-Hua Chui, Takumi Akagi, Kenichi Mishima, Katsunori Iwasaki, Michihiro Fujiwara, Kentaro Tanemura, Miyuki Murayama, Koichi Ishiguro, Emmanuel Planei, Shinji Sato, Tsutomu Hashikawa, amd Akihiko Takashima: "Tau f

馆林喜孝、宫坂智博、崔德华、赤木拓海、三岛健一、岩崎克典、藤原道宏、种村健太郎、村山美雪、石黑浩一、伊曼纽尔·普拉内、佐藤真司、桥川勉、高岛明彦：“Tau f