阿尔兹海默病（AD）的神经血管假说表明脑内神经血管单元（NVU）异常可启动AD发病级联但致病机制尚未阐明。临床流行病学研究证实衰老是AD的最大危险因素。Klotho（KL）衰老抑制基因缺陷小鼠出现痴呆、动脉粥样硬化等表型改变，其机制可能与衰老过程KL调控的信号转导通路功能障碍有关。新近报道AD患者脑脊液中KL明显减少；申请人发现AD小鼠KL表达水平与AD病变程度呈显著负相关，而川芎苯酞类化合物藁本内酯通过调节KL表达及KL调控的IGF-1通路，明显减轻小鼠的AD病变。本项目拟制备系列川芎苯酞类化合物，靶向KL基因表达的活性筛选，以高活性的苯酞化合物为药物探针分子，结合KL基因的细胞转染技术，研究KL对AD病程中NVU的调控作用与分子机制。本研究工作将有助于深入解析衰老与AD高度关联性的分子基础、探寻防治AD的潜在药物靶点、发现防治AD的新型候选药物或先导化合物，具有重要的科学意义。

The neurovascular hypothesis of Alzheimer's disease (AD) suggests that the abnormality of cerebral neurovascular unit (NVU) induces the AD pathogenic cascades, however, the underlying mechanisms remain unclear. Clinical epidemiological studies confirm that aging is the major risk for the development of AD. Aging-suppressor gene Klotho deficiency in mice displays several aging-like phenotypes, such as dementia and atherosclerosis, which is probably associated with the dysfunction of Klotho-regulating signaling transduction pathways. Recent study shows that Klotho levels are lower in cerebrospinal fluid of AD patients compared with controls without AD. In addition, applicant finds that there is a significant inverse correlation between Klotho expression and AD phenotype in mice, and phthalide ligustilide from Rhizoma chuanxiong significantly ameliorates AD-like impairment in mice through regulation of Klotho expression and IGF-1 signaling pathway. This project will prepare series of phthalides from Rhizoma chuanxiong, screen their activity targeting Klotho gene expression. The regulation and underlying molecular mechiansims of Klotho on NVU during the pathogenic process of AD will be investigated by phthalide probe molecules with high activity and cell transfection of Klotho gene. This study will make a contribution to elucidation of molecular basis of high correlation between aging and AD, exploration of potential drug targets against AD and discovery of novel candidates or leading compounds for AD threatment and prevention in future.