慢性牙周炎和阿尔茨海默病的相关性研究：淀粉样前体蛋白及代谢物的双向调节作用初探

Chronic periodontitis (CP) is a multifactorial inflammatory disease that is initiated by the accumulation of dental plaques and destroys the dental attachment apparatus. As numerous epidemiological associations link CP to multiple systemic conditions, it is much attention to periodontal medicine. Alzheimer's disease (AD) is the most common cause of primary degenerative dementia among elderly people, which has emerged as a major health concern in elderly people worldwide. Although an increasing number of clinical studies have recently demonstrated CP may be a potential risk factor for AD, there still lacks sufficient experimental studies in support of the relationship between CP and AD. So, it is necessary to explore their relationship and underlying mechanisms in detail. .Our previous study has found that periodontal inflection by Porphyromonas gingivalis caused the decrease of distance and short of time spent in target quadrant in probe trials. High expression of amyloid precursor protein (APP) occurred in CP samples. APP/PS1 mutated transgenic mice also showed the progressive destruction of alveolar bone and high expression of APP in periodontal supporting tissue. These data indicated that there maybe exist associations to some degree between CP and AD. The present study will further focus on the APP processing, the key pathological characteristic of AD, in order to investigate the potential roles of APP in the connections between CP and AD. Firstly, behavior evaluation and neuron-vessel unit will be used to study the effect of periodontitis-related pathogen on APP processing and consequently cognitive function. Secondly, the roles of APP and its metabolite in CP pathological progression will be investigated using collection of clinical samples, periodontal cell cultures, and APP/PS1 mutated transgenic mice. .In conclusion, our study will elucidate the connections between CP and AD through bidirectional regulation of APP and its metabolite. It may give us chances to have a better understanding of pathological mechanisms about CP and AD. It also may provide novel insights into the periodontal treatment to prevent AD and delay the development of AD and bring about the development of novel therapeutic interventions for AD.

随着牙周医学兴起，探讨慢性牙周炎(CP)和系统性疾病的双向关联机制已成研究热点。阿尔茨海默病(AD)是最常引起老年人痴呆的神经退行性病变，社会老龄化使AD成为老年医学面临的最严峻问题。仅有临床调查提示CP可能是AD的危险因素，但CP和AD双向关联尤其关联机制尚缺乏充分的实验研究支持。课题组前期发现牙周接种牙龈卟啉单胞菌影响鼠空间探索能力；CP牙龈标本APP高表达；AD模型鼠牙槽骨破坏；初步提示二者相互关联。本研究进一步聚焦AD关键靶标淀粉样前体蛋白(APP)及代谢物，从整体行为、神经血管单元、临床标本、和牙周组织，系统研究牙周致病菌对脑APP代谢的调节和认知影响；以及APP和代谢物在牙周病变中的作用及机制。以期阐明CP是影响神经认知的危险因素，APP及代谢物可调控CP病理进程，即二者双向关联。这不仅加深CP和AD病理机制的理解，也为探寻牙周干预策略延缓AD发生发展提供实验依据和理论支持。

随着牙周医学兴起，探讨慢性牙周炎(CP)和系统性疾病的双向关联机制已成研究热点。社会老龄化使老年痴呆成为老年医学面临的最严峻问题。虽然临床调查提示CP可能是AD的危险因素，但是CP和AD双向关联尤其关联机制仍缺乏充分的实验研究支持。本项目围绕慢性牙周炎和阿尔茨海默病的关联机制，聚焦AD关键靶标淀粉样前体蛋白(APP)及代谢物，探讨了牙周炎重要致病因子牙龈卟啉单胞菌(P.gingivalis)对脑认知功能的影响，以及对神经血管单元APP代谢的影响；检测慢性牙周炎标本及牙周相关细胞APP代谢的变化；也观察了AD模型小鼠牙周的变化，并制备Aβ单体及寡聚体，观察对牙周致病菌以及牙周细胞的影响。. 结果表明，腹腔注射牙龈卟啉单胞菌脂多糖(P.gingivalis-LPS)后可显著损害小鼠空间学习和记忆能力以及被动回避的反应记忆能力。大鼠龈沟注射P.gingivalis-LPS可造成牙周炎样改变；行为学测试显示大鼠的空间学习和记忆能力受损；脑内促炎因子水平上调、抗炎因子水平下调，小胶质细胞和星形胶质细胞被激活表现出神经炎症；通过调节APP代谢途径促进Aβ的生成和沉积，促进AD样的病理进程。体外实验也显示，P.gingivalis-LPS可调节神经细胞APP家族相关基因表达，影响APP代谢关键酶，促进Aβ的生成。. 另外，在慢性牙周炎标本中发现牙周组织APP家族相关基因以及APP代谢关键酶的表达，龈沟液中检测到Aβ1-40和Aβ1-42，证实了APP及代谢物参与牙周炎的病理进程。AD模型小鼠呈现牙周骨组织吸收，骨密度下降。Aβ单体及制备的寡聚体，对牙周致病菌以及牙周膜细胞有抑制作用。. 综上，慢性牙周炎可能是脑认知损害的危险因素，与AD发生发展具有相关性。APP及代谢物不仅与认知损害密切相相关，可能在牙周炎病理进程中发挥一定作用。本项目深入探讨了牙周炎与认知功能之间的关系，这不仅为探寻牙周干预策略对延缓AD发生、发展提供实验依据和理论支持，也为寻找AD预防、治疗的靶点提供新思路和新方法。