利用PET/MR探讨肠道微生物对阿尔茨海默病老年斑形成效应的机制

Alzheimer's disease (AD) is the most common dementia, its pathologic hallmark is the formation of senile plaque, in which β-amyloid peptide (Aβ) is a major component, and its mechanism has still not completely been unreveiled. Studies revealed that alteration of gut microbiota could alter cognitive function and reduce the formation of senile plaques in aging individuals, but little understanding on the mechanism of regulating cognitive function of AD via gut microbiota is also unknown. PET/MR is an ideal molecular technology to study brain variation in animal model and patients in vivo. Based on our previous results, our hypothesis is that gut microbiota may modulate the formation of Aβ in brain by changing interleukin (IL)-33. Therefore, this study will include studies on AD patients and APP/PS1 double transgenic mouse. We will get the potential pathogenic bacteria and probiotic bacteria, which are easily cultivated in vitro, from AD patients and healthy controls, and cultivate those bacteria and transplant them into APP/PS1 double transgenic mice. Then, to assess the effect of those pathogenic and probiotic bacteria on the formation of senial plaque via utilizing PET/MR. Meanwhile, IL-33 level in surum and brain will be checked in APP/PS1 mice. The results will offer a new target and new way of treating AD, and provide the base and envidence for further clarifying the mechanism of gut microbiota in pathogenesis of AD.

阿尔茨海默病(AD)是最常见的一种老年性痴呆，脑内老年斑的形成是其重要的病理学特征，其机制尚未完全明了。研究显示通过改变肠道微生物能够改善老年认知功能和减少老年斑的生成。PET/MR技术同时具有PET和MR的优势，能够从分子影像学角度观察大脑功能变化，是研究活体大脑变化的最佳工具。本课题科学假说是，肠道微生物通过改变体内IL-33水平，影响老年斑的生成。本项目利用PET/MR技术有助于从分子影像角度精确定量分析肠道微生物对AD老年斑的效应。项目组在前期研究基础上，通过临床试验确定AD组和健康对照组的致病菌和益生菌，培养并移植到APP/PS1双转基因AD模型小鼠中，观察这些致病菌和益生菌对模型小鼠老年斑形成的效应及其机制。本结果将为AD的临床治疗提供新途径，为进一步阐明肠道微生物参与AD发病机制提供基础资料。

肠道微生物与环境应激相互作用是老年性痴呆的发病重要因素。本研究致力于探讨其对老年性痴呆早期发病中的重要作用和可能的机制。.1.首次发现AD组中若干细菌(13种)不同于HC组。对于进一步研究肠道微生物人体内在重要的环境因素在AD中的重要价值。AD患者和健康对照者的肠道微生物组的构成不完全一致，且外周血中的sST2、IL-33以及Aβ42的变化也不完全一致(p<0.05)。.1）AD组的parabacteroides/副细菌类, klebsiella/克雷伯菌, lactobacillus/乳酸杆菌, fastidiosipila/梭菌科菌, alloprevotella/拟普雷沃菌属, anaerotruncus/厌食杆菌, mogibacterium, anaerococcus/厌氧球菌, collinsella/柯林斯菌属, parvinonas占有优势；HC组的lachnospira/鼻螺旋菌微氧环境占有优势。.2）AD组sST2和BDNF的浓度低于HC组，在Aβ42、TNF-α、IL-10、IL-6、IL-18高于HC组。.3）AD组MMSE总分与sST2正相关，与Aβ42、TNF-α、IL-6、IL-18负相关。ADAS-cog总分与sST2正相关，与Aβ42、TNF-α、IL-6、IL-10、IL-18负相关。ADAS-cog对于AD评估更敏感。.2、证实了klebsiella（条件致病菌）可能加速老年斑的形成。.3、项目组发现AD患者前期的大脑功能有异常，尤其是失眠和抑郁症状明显。故项目组调整思路，针对该群体的失眠和抑郁症状进行积极干预，建立了经颅交流电治疗失眠和抑郁症状的物理治疗方法，为AD的非药物治疗提供基础。.目前发表了相关文章7篇，其中，第一标注影响因子>10分的研究论著2篇。