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

摘要 此申请是对P51灵长类研究中心拨款的补充，该基金支持 华盛顿国家灵长类研究中心。本补充资料将用于开展为期1年的 初步研究建立一个新的研究计划来表征两者之间的联系 炎症和年龄相关的猴子认知能力和口腔健康的变化 (猕猴)。猴子为我们提供了一个强有力的模型来促进我们对 人类记忆和执行功能的神经生物学研究 内侧颞叶和前额叶皮质的解剖和连通性。积累 有证据表明认知障碍和系统免疫之间存在联系。 激活。血清促炎细胞因子水平的升高已被证明与 与认知障碍有关，这种炎症与认知的联系已经在 其他健康的老年人。伴随着炎症-认知、炎症-口腔健康 这种关联在老年人中也表现为牙周病(PD)，即 影响近70%65岁以上美国成年人的慢性炎症性口腔疾病 导致口腔微生物群失调，牙龈上皮和牙周骨遭到破坏 最终导致牙齿脱落。帕金森病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，而慢性牙周病患者有更高的 罹患痴呆症的风险。我们最近发现，特异性mTOR抑制剂雷帕霉素 导致老的口腔微生物组的逆转移动，使其与年轻的口腔微生物组更相似 在小鼠中，可减轻牙龈和牙周组织的炎症，并逆转牙周骨 在老动物身上的损失。因此，该提案的首要目标是(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)证实 老年恒河猴作为自然牙周病模型的实验研究 MTOR抑制对与年龄相关的口语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.