阿尔兹海默症(AD)是造成痴呆的主要原因，它的主要病理特征是记忆丧失，认知能力衰退，胞外Aβ蛋白聚集，神经纤维缠结等最终引起神经元变性死亡。Aβ寡聚体诱导产生的学习障碍和AD发生密切相关。 通过机制探寻方式我们发现临床上使用的EGFR抑制剂则不仅改善了Aβ42果蝇模型的学习能力，还可以显著提高APP〓和PS1〓双转基因AD小鼠的学习记忆能力。通过大规模筛选具有潜在激酶活性的小分子化合物过程中，我们发现有3个化合物能同时挽救AD果蝇和小鼠的学习记忆缺陷。其中有1个可以有效降低Aβ寡聚体诱导的EGFR异常的磷酸化。这些结果都强有力的证明了EGFR是治疗Aβ引起学习障碍的潜在靶点。 Rac1可以通过EGFR／PI3K／Akt通路激活从而行使其生理功能。越来越多的证据显示Aβ42通过不同的途径激活小G蛋白Rac，但是具体的机制还不清楚。在果蝇和小鼠的AD动物模型以及AD患者海马区，免疫印迹结果均显示Rac1-GTP蛋白水平异常增加。通过药物学和遗传学方法降低Rac1活性可以改善Aβ42果蝇模型和APP〓和PS1〓双转基因AD小鼠的学习记忆能力。EGFR抑制剂Gefitinib同样可以抑制Aβ导致的异常增高的Rac1活性。年轻的Aβ42果蝇惩罚性嗅觉学习曲线和年轻的双转基因AD小鼠空间的短时程记忆结果显示他们的记忆获取功能是正常的，和对照果蝇和小鼠相比AD动物模型的记忆衰减加快。因此，我们推测AD早期的学习缺陷可能是Rac1介导的主动遗忘导致的。 课题另一个重要的工作是发现7个化合物可以显著改善Aβ42引起的早起认知功能损伤。他们对AD相关药物开发有很大的潜力。 关键词：阿尔兹海默症；淀粉样蛋白β；表皮生长因子受体；小G蛋白Rac；认知功能障碍

 Alzheimer's disease (AD) as a major cause of dementia is characterized by memory loss, cognitive decline, Aβ accumulation, the formation of tangle and eventual neurodegeneration. Amyloid-β oligomers-induced memory loss is thought to contribute to AD progression. Mechanism-guided approach led to the finding that clinically available EGFR-inhibitor was effective in treating the Aβ-induced memory loss in Aβ42-expressing transgenic flies and double transgenic mice. Behavioral screening of 2000 synthetic compounds presumably targeted to protein kinase activities identified 4 effective compounds in rescuing the Aβ-induced memory loss in the fly and mouse model. 1 out of 4 was capable of inhibiting the oligomeric Aβ-induced activation of human EGFR expressed in cultured COS-7 cells. Taken together, strong evidences presented support that EGFR is a preferred target for treatment of Aβ-induced memory loss. EGFR/PI3K/Akt pathway is upstream of Racl to exert its pathological function. There is mounting evidence that Aβ42 stimulates Racl, a small G protein, through several pathways in vitro and vivo test, however the function of activation is still obscure. Significant higher levels of Racl-GTP were observed in the presence of Aβ42 in AD models and patients. Then we manipulated Racl activity by pharmacological and genetic approaches in AD fly and mice model and found the defect of learning could be ameliorated. Also Gefitinib treatments significantly rescued the activation of Racl. Then we detected the olfactory aversive learning and spatial short term memory in AD models at young ages. We found the acquisition of memory was intact, but there was more rapidly memory decay compared with control. Those data indicated Racl mediated active forgetting contributed memory loss in early stage of AD. An important finding of this work is the efficiency of seven compouds in treating Aβ42-induced cognitive deficits and these chemicals are potential drugs for AD treatment. Key words: Alzheimer's disease; Amyloid-β; Epidermal growth factor receptor; Small G protein Rac; Cognitive deficits