Endothelial Metabolic Autophagy Mechanism of Vascular Dementia in Periodontopathic Infection

最近的研究强调了血管对认知损害和痴呆(VCID)的贡献 阿尔茨海默病和相关痴呆(AD/RD)认知功能障碍的主要因素。在……里面 同时，越来越多的证据也强调了共同疾病的病理学指向多因素疾病的病因。 慢性牙周炎在美国影响着47%的30岁及以上的成年人，最近与 AD/RD和牙周主要微生物牙龈卟啉单胞菌的风险增加 建议作为AD领域的独立风险修饰符。我们的研究小组和其他人最近的研究 强调活体牙龈假单胞菌从牙龈粘膜到深层的潜在系统重新定位 通过强烈的微血管形成的组织。此外，从AD患者的大脑样本中分离出该细菌，并 几个实验模型表明牙龈假单胞菌特异性地参与了牙周炎的标志性细胞病理学 广告/研发然而，在AD/RD的时间发展中仍然存在显著的知识差距，因为 AD/RD的标志性分子标记本身不足以引起这些疾病，而 近一半的患者还表现出VCID和AD病理的混合特征。使用此管理程序 作为补充，我们提出了新的中心假设，即牙龈假单胞菌的慢性感染针对的是 神经血管单位增加了VCID的致病性，并导致AD/RD的早期发病。我们 具体假设牙龈假单胞菌对脑内皮细胞谷氨酰胺代谢途径的改变 其通过氧化还原失衡与缺陷细胞自噬的偶联是AD/RD的早期病理生理过程。 因此，该补充应用程序的直接目标是启动概念验证临床前模型 从机械角度探讨牙龈假单胞菌在神经血管病理发展中的新作用 和渐进性认知衰退，可以有针对性地预防。这使得牙龈假单胞菌成为 这是一个重要的研究课题，特别是在高危人群继续老龄化和增长的情况下。通过将我们的 Ergul博士在牙龈假单胞菌细胞生物学方面的独特专业知识，他是临床科学家，也是 认知衰退/痴呆的基础神经血管病理生物学，我们的长期目标是 建立强大的基础翻译研究计划，重点关注针对并存疾病的早期干预策略 慢性牙周炎的认知障碍/痴呆。

Recent research highlights the vascular contributions to cognitive impairment & dementia (VCID) as a leading factor of the cognitive disfunction identified in Alzheimer’s Disease and Related Dementias (AD/RD). In conjunction, growing evidence also underlines co-morbid pathology pointing to multifactorial disease etiology. Chronic periodontitis, which affects 47% of adults aged 30 years and older in the U.S. is lately associated with the increased risk of AD/RD and the major periodontal microorganism, Porphyromonas gingivalis has been proposed as an independent risk modifier in the AD field. Recent studies from our research group and others emphasize the potential systemic relocation of the live P. gingivalis from the gingival mucosa to the deeper tissue via intense microvasculature. Further, the bacterium was isolated in the AD patients’ brain samples, and several experimental models proposed P. gingivalis’ specific involvement in the hallmark cellular pathologies of AD/RD. However, significant knowledge gap still exists in the temporal development of AD/RD, since the hallmark molecular markers of the AD/RD are not sufficient by themselves to cause these disorders, while nearly half of the patients also manifest mixed features of VCID and AD pathologies. With this administrative supplement, we propose the novel central hypothesis that chronic infection by P. gingivalis targeting the neurovascular unit increases the pathogenicity of the VCID and leads to an earlier onset of the AD/RD. We specifically postulate that alteration of the brain endothelial glutamine metabolic pathways by P. gingivalis and its coupling to defective cellular autophagy via redox imbalance is an early pathophysiology in AD/RD. Thus, the immediate goal of this supplemental application is to initiate proof-of-concept preclinical models mechanistically addressing the emerging role of P. gingivalis to the development of neurovascular pathology and progressive cognitive decline that can be specifically targeted for prevention. This makes P. gingivalis an important topic of study, especially as the at-risk populations continue to age and grow larger. By merging our unique expertise in the cellular biology of P. gingivalis with Dr. Ergul, a clinician scientist and leader in the basic translational neurovascular pathobiology of cognitive decline /dementia, our long-term goal is to build a robust basic translational research program focusing on early intervention strategies against comorbid cognitive impairment /dementia in chronic periodontitis.