妊娠期母体暴露脂多糖对子代发生阿尔茨海默病及其表观遗传修饰机制的研究

Alzheimer's disease(AD) is the most common cause of dementia and has high prevalence and morbidity, which constitutes a tremendous social and economical problem. But, the initiation and development of AD remain unclearly elucidated. Currently, it is agreed that the dual role of genetic and environmental factors may be the underlying cause of the onset of sporadic AD. In recent years, "fetal origins of adult diseases" hypothesis suggests that many chronic diseases of adulthood originate from the adverse factors exposure in the embryonic period and the molecular mechanism may be epigenetics. This hypothesis ascribes the majority of chronic disease etiology to prenatal exposure to adverse factors, but whether it has implication for AD is controversial. Our previous studies showed that maternal exposure to lipopolysaccharide during pregnancy accelerated age-related learning and memory decline in offspring mice. These results indicate that prenatal exposure to infection might lead to the occurrence of AD. But this viewpoint has not been directly demonstrated and its mechanism has not been explored. The present study is to further explore the effect of embryonic exposure to infection on the incidence of AD in old age of mice. In the whole experimental process, the growth, development and the maturation of the nervous system will be dynamically detected. Meanwhile, behavioral device will respectively assess the behavioral changes in middle or old age. Moreover, the pathophysiology of AD (such as senile plaque, neurofibrillary tangles and hyperphosphorylation of tau), DNA CpG methylation,histone acetylation and their related enzymes will be tested in the hippocampus and cerebral coxtex by different methods. Therefore, the present study is to verify the fetal origins of sporadic AD and explore its epigenetic mechanism, which may provide a scientific basis to prevent and cure AD.

阿尔茨海默病（AD）具有高患病率和致残率，危害极大，然而其始动和持续进展机制未明。近年提出的"成人疾病胎源学说"及其表观遗传修饰机制适用于某些慢性疾病，但其能否用于AD尚无定论。本课题组前期研究证实妊娠期母体暴露脂多糖可加速中年CD-1子鼠出现年龄相关性学习记忆能力减退，结合其它相关研究我们推测妊娠期母体暴露脂多糖可能会导致子代AD的发生，但未获直接证据且未探索其可能发生的机制。本研究拟进一步利用母鼠孕期暴露脂多糖来观察对子代老年期发生AD的影响。整个过程检测小鼠生长发育和神经系统成熟情况，及至小鼠中、老年期分别进行行为学评估，并检测AD相关的病理生理改变（如老年斑、神经原纤维缠结、tau蛋白过度磷酸化），及测定大脑皮质和海马AD相关基因的启动子区域CpG岛甲基化水平、组蛋白乙酰化和相关酶类，以验证散发性AD 发生的"胎源学说"并探讨其可能发生的表观遗传修饰机制，为AD防治提供理论依据。

阿尔茨海默病（AD）具有高患病率和致残率，危害极大，然而其始动和持续进展机制未明。近年提出的“成人疾病胎源学说”及其表观遗传修饰机制适用于某些慢性疾病，但其能否用于AD尚无定论。本课题组结合以往的相关研究推测妊娠期母体暴露脂多糖可能会导致子代AD的发生，但未获直接证据且未探索其可能发生的机制。本研究利用母鼠孕期暴露脂多糖来观察对子代老年期发生AD的影响。整个过程检测小鼠生长发育和神经系统成熟情况，及至小鼠中、老年期分别进行行为学评估，并检测AD相关的病理生理改变，及测定大脑皮质和海马AD相关基因的启动子区域CpG岛甲基化水平、组蛋白乙酰化和相关酶类，以验证散发性AD 发生的“胎源学说”并探讨其可能发生的表观遗传修饰机制。本研究结果表明孕晚期母体暴露适量的LPS后，子代可经过正常的出生、发育和成熟，到中老年期出现了较为显著的衰老加速，表现为类AD样改变即LPS处理的子鼠中年时焦虑活性开始增加，空间学习记忆能力和再认记忆能力开始出现下降，老年时体能和种属行为能力开始下降，至高龄时各功能域损害更明显。此外，子鼠脑内病理生理也有类AD样改变，表现为LPS处理的中老年期子鼠海马出现了更严重的Aβ1-42和p-tau负荷升高，星形胶质细胞活化增生及突触活性带蛋白表达的改变（如syntaxin1和PSD95含量降低、Syt1含量增加），这些改变随着年龄增长而逐渐加重，而表观遗传学修饰机制可能参与了这些改变的发生发展过程中，主要有LPS处理的子鼠海马H4K8和/或H3K9乙酰化及H3S10磷酸化程度降低，而H3K9三甲基化程度及组蛋白去乙酰化酶2水平升高，随着年龄增长愈加明显（范围扩大、程度增加）且与暴露的剂量有关。慢性应激会协同恶化上述多数LPS处理的行为学、病理生理学和表观遗传学改变，而丰富环境则会延缓这些改变。此项研究为正确理解散发性AD的病因提供更复合的信息，也给积极有效防治提供理论依据。