Endothelial Metabolic Autophagy Mechanism of Vascular Dementia in Periodontopathic Infection

近年来的研究强调血管在认知障碍和痴呆（VCID）中的作用

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.