阿尔茨海默氏病（AD）是最常见的慢性神经系统变性疾病，分家族性和散发性两种类型，后者占95%。近年来抗AD药物研发不断宣告失败，发病机制不完全清楚和现有动物模型不能很好的模拟散发性AD临床病程是两大主要原因。因此，建立散发性AD的新型动物模型显得非常迫切。AD患者脑内脂质代谢中间产物丙烯醛的水平升高。申请人发现，丙烯醛能够诱导大鼠AD样病理改变。基于此，我们提出三个科学问题：1，丙烯醛诱导大鼠脑AD样病理改变与哪些因素有关？2，丙烯醛能否诱导食蟹猴脑的AD样病理改变及其影响因素是什么？3，丙烯醛诱导动物模型的分子机制是什么？为回答这些问题，本项目拟：1，建立基于丙烯醛的新型散发性AD大鼠和食蟹猴模型、考察影响因素并对模型建立和评价方法标准化；2，研究丙烯醛诱导动物模型的分子机制以揭示AD的发病机制。本项目对AD机理研究，药物新靶点发现以及临床前药效学评价都将具有十分重要意义。

Alzheimer’s disease (AD) is the most common chronic neurodegenerative disease and is divided into two forms, familial AD (fAD) and sporadic AD (sAD). In contrast to the rare familial form, 95% AD patients are suffered from sAD. However, the unclear pathogenesis of AD and the restriction of animal models in simulating the clinical process result in the consecutive failure of anti-AD drug development. Therefore, developing novel sAD animal models is of great significance. The level of acrolein, an intermediate of lipid metabolism was increased in AD patients and we have demonstrated that acrolein could induce the AD-like pathological changes in rat brain. Based on the above, we raise 3 questions: 1，What are the factors influencing the acrolein-induced AD-like pathological changes in rat brain? 2，Does acrolein induce AD-like pathological changes in Macaca Faiscularis and what are the influencing factors? and 3, What is the underlying molecular mechanism(s) that acrolein can induce AD animal models? In order to answer these questions, we first plan to establish new sAD models induced by acrolein in rats and Macaca Faiscularis, to investigate the influencing factors and to standardize the methods of model establisment and evaluation. Then we plan to study the exact mechanism(s) of acrolein-induced animal models to reveal the pathogenesis of AD. The current project is of great importance in AD development mechanism exploration, anti-AD drug target validation and preclinical pharmacodynamic evaluation.