The Relationship between Inflammation and Cognition in a Monkey Model of Human Aging

摘要 此申请是对P51灵长类动物研究中心资助的补充，该资助支持 华盛顿国家灵长类动物研究中心。该补充将用于进行为期1年的 试点研究，以建立一个新的研究计划，以确定 炎症和年龄相关的猴子认知能力和口腔健康的变化 （恒河猴）。猴子提供了一个强有力的模型，以促进我们的理解， 人类记忆和执行功能的神经生物学，由于强大的跨物种相似性， 内侧颞叶和前额叶皮层的解剖学和连通性。积累 有证据表明，认知障碍和全身免疫系统之间存在联系， activation.促炎细胞因子的血清水平升高已被证明与 认知障碍，这种炎症认知协会已被证明， 健康的老年人。沿着炎症-认知，炎症-口腔健康 在老年人中也以牙周病（PD）的形式证明了这种关联， 慢性炎症性口腔疾病影响近70%的65岁以上的美国成年人， 导致口腔微生物群失调，破坏牙龈上皮和牙周骨 最终导致牙齿脱落。PD也是其他几种与年龄相关的疾病的主要风险因素， 包括心脏病和糖尿病，而慢性牙周病患者 患痴呆症的风险。我们最近发现特异性mTOR抑制剂雷帕霉素 导致旧的口腔微生物组的逆转转变，使其与年轻的口腔微生物组更相似 在小鼠中，减轻牙龈和牙周组织炎症，并逆转牙周骨 老动物的损失因此，本提案的总体目标是（1）确定是否 促炎细胞因子水平升高与认知能力下降有关，（2）建立 老年恒河猴作为自然发生牙周病模型，和（3）分析 mTOR抑制对年龄相关的口腔和认知能力下降的直接影响。

ABSTRACT This application is for a supplement to the P51 Primate Research Center Grant that supports the Washington National Primate Research Center. This supplement will be used to conduct a 1-year pilot study towards establishing a new research program to characterize the association between inflammation and age-related changes in cognitive performance and oral health in monkeys (rhesus macaques). Monkeys provide a strong model for advancing our understanding of the neurobiology of human memory and executive function due to robust cross-species similarities in the anatomy and connectivity of the medial temporal lobe and prefrontal cortex. Accumulating evidence has suggested an association between cognitive impairment and systemic immune activation. Elevated serum levels of pro-inflammatory cytokines have been shown to be related to cognitive impairment, and this inflammation-cognition association has been demonstrated in otherwise healthy older individuals. Along with inflammation-cognition, inflammation-oral health association is also demonstrated in older individuals in the form of periodontal disease (PD), a chronic inflammatory oral disease affecting nearly 70% of U.S. adults over the age of 65 which leads to a dysbiotic oral microbiome, destruction of the gingival epithelium and periodontal bone with ultimately tooth loss. PD is also a major risk factor for several other age-related disorders, including heart disease and diabetes, and patients with chronic periodontal disease have a higher risk of developing dementia. We recently discovered that the specific mTOR inhibitor rapamycin caused a revertive shift of the old oral microbiome to be more similar to the young oral microbiome in mice, attenuated gingival and periodontal tissue inflammation, and reversed periodontal bone loss in old animals. Thus, the overarching goals of this proposal are to (1) determine whether elevated levels of pro-inflammatory cytokines are associated with cognitive decline, (2) establish the aged rhesus monkey as a model for naturally occurring periodontal disease, and (3) analyze the direct impact of mTOR inhibition on age-related oral and cognitive decline.