临床研究表明载脂蛋白E4（ApoE4）不仅是阿尔茨海默病（Alzheimer Disease，AD）的主要遗传危险因素，而且加速了年龄相关性认知功能下降，但具体机制尚不明确。海马组织的神经发生与海马依赖型的学习记忆功能密切相关，老化过程中端粒酶/端粒在调控神经发生的过程中发挥了关键性的作用。我们的前期研究发现ApoE4能加速C57BL/6J小鼠的学习记忆功能的增龄性下降、减低海马组织端粒酶活性催化亚基mTERT表达水平。本研究拟以ApoE-KO和ApoE3-TR小鼠为对照，通过体内研究和体外培养成年海马神经干细胞的方式，动态连续观察ApoE4对神经干细胞端粒酶活性、端粒长度及神经发生的影响；同时探讨bexarotene上调ApoE4表达对神经干细胞表达端粒酶活性和神经发生的影响。本研究将有助于进一步认识ApoE4增加年龄相关性认知功能障碍的可能机制，为老年期认知功能障碍的研究提供新的思路。

Clinical studies have shown that apolipoprotein E4 (apoE4) is not only the main genetic risk factors for Alzheimer’s Disease (AD), and accelerated the age related cognitive decline, but the mechanism is unclear. Adult hippocampus neurogenesis is closely correlated with hippocampus-dependent memory performance. Telomerase/telomere has played a key role in modulating neurogenesis during aging. In our preliminary experiment, we found that ApoE4 has accelerated age related cognitive decline in C57BL/6J mice and decreased the level of mRNA of telomerase reverse transcriptase (Tert) in hippocampus. In this study, ApoE-KO mice and ApoE3-TR mice for comparison, the effect of ApoE4 on telomerase activity and telomere length of neuronal stem cell and neurogenesis in hippocampus will be dynamically observed in vivo and in vitro culture of adult neuronal stem cells. Furthermore, ApoE4 expression induced through bexarotene, effect increasing ApoE4 on telomerase activity in neuronal stem cell and neurogenesis will be further investigated. Overall the proposed work will help to illustrate the mechanism which ApoE4 accelerated age related cognitive decline and provide a new idea for studying old age cognitive dysfunction in future.