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

淀粉样蛋白(β-β，A-A)沉积在老年斑中，被认为是阿尔茨海默病(AD)的主要原因。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(R406W)在10月龄时表现出行为抑制，SSRI抑制了这一行为。提示5-羟色胺能机制在AD早期可能起重要作用。(2)非转基因AD动物模型对于新药开发也是必要的。首先，我们利用8臂放射状迷宫任务建立了短暂性脑缺血与脑内注射Aβ1-42相结合的治疗方法。Aβ1-42治疗大鼠和脑缺血大鼠在第7天的保持试验中均未表现出记忆障碍。另一方面，Aβ1-42与10 mm缺血的联合治疗显示出明显的空间记忆障碍。鉴于AD在绝经后妇女中的发病率较高，我们联合去卵巢和脑内注射Aβ1-42对雌性大鼠进行了研究。Aβ1-42与去势联合治疗也能明显延缓8臂放射状迷宫大鼠血清雌激素水平的下降，并表现出记忆障碍。对这两种模型的进一步研究表明，Aβ诱导的海马区细胞凋亡和ACh功能障碍可能导致AD的痴呆，而药物抑制这些症状可能有助于AD的治疗。

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.