The role of oral microbially induced exosomes in Alzheimer's disease pathogenesis

Alzheimer’s disease and related dementia (ADRD) affect 50 million people worldwide with no effective cure. Currently, more than 6.2 million Americans aged 65 years and older are suffering from AD, with a projection of that number doubling in 2060. A role for infectious disease in the pathogenesis of AD has long been proposed with viruses such as HSV and, more recently gingipains of the oral pathogen Porphyromonas gingivalis (Pg), detected in the brains of AD patients postmortem. There is a strong epidemiologic association between periodontitis (PD) and AD but how these two diseases intersect, and whether it is at the level of causation is unclear. Recent evidence shows a role for Pg and its potent proteases gingipains in AD pathology, however, definitive evidence for presence of Pg whole bacterium in the brain tissues is lacking and the precise mechanism of microbial invasion of BBB is not clearly understood. The blood-brain barrier (BBB) is highly vulnerable to penetration by exosomes, nano-sized membrane-enclosed particles that originate in the cellular endocytic pathway and are secreted in the extracellular space. Cellular senescence is known to increase exosome biogenesis and secretion as part of the senescence-associated secretory pathway (SASP). Exosomes derived from senescent cells can in turn transport molecular cargo that may induce senescence in bystander cells. Our work has shown that dendritic cells (DC), a highly migratory immune cell that resides in the oral mucosal barrier, are vulnerable to invasion by Pg. Moreover, this activates the SASP, consisting of inflammasome-related cytokines and exosomes. The resulting exosomes contain Pg antigens, gingipains and fimbriae adhesin proteins, which locally transmit and amplify immune senescence to bystander immune cells. Our central hypothesis is that exosomes released into gingival tissues during PD infection cross the BBB and induce senescence and neuroinflammation, contributing to AD pathology and cognitive impairment. Our preliminary data provide a strong rationale for this hypothesis. We show using AD mouse models [APPNL-G-F Knock-in and 5XFAD] and P163MR reporter mice that oral microbially induced exosomes secreted from gingival tissues of PD murine models in-vivo (PD-exo), cross the BBB to induce senescence, neuroinflammation, and AD pathology. Particularly intriguing new data support the presence of these Pg-induced exosomes in postmortem brain tissue of AD patients. In this proposal, we present a novel mechanism of oral microbiome-brain tissue crosstalk in the infectious etiology of AD.