Porphyromonas gingivalis outer membrane vesicles as the major drivers of and source for the toxic insult and iron accumulation/deposition in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neuroinflammatory and neurodegenerative disease of the brain, defined by the accumulation and deposition of beta-amyloid, which has recently been identified as an antimicrobial peptide suggesting an infectious etiology. The NIH's Institute on Aging recently announced new initiative to look for alternate etiologies for AD that included a call for the better understanding of the role of peripheral verses local infections, as well as sources of both local and systemic inflammation. Proving if in the case of an oral bacteria that it is migrating from the oral cavity to the brain verses whether the peripheral oral source of the bacteria are instead mostly secreting toxic gingipains/LPS/complexes in soluble or as OMVs is central to understanding the pathogenesis for this disease including their role in iron toxicity in neurovascular disease and AD.A hypothetical model of Porphyromonas gingivalis (Pg) is put forth to address if: 1. either translocation to the brain from the oral cavity via blood lymphatics, intracellularly or via neuronal axoplasmic flow and establishing a productive infection of the brain leading to the local production and the accumulation of Pg exo-/endo-toxins (e.g. gingipains/LPS etc.) verses; 2. the oral peripheral infection/colonization in the oral cavity shedding exo-/endo toxins and other virulence factors as either soluble forms or associated with complex actively secreted outer membrane vesicles (OMVs) into the blood and/or lymphatics and trans-migrating the neuro-vascular endothelium with entry into the neural parenchyma and its association with iron are important and notable differences in both pathogenesis of disease and the focus of treatment.As follows.Overviewing all published papers on natural cases of human AD or murine experimental models of Pg suggest strongly that despite in the experimental case of very large and prolonged oral admisntrastion, little direct evidence is presented to support that metabolically active bacteria reside in the brain and are responsible for the production of the toxic by-products therein. A review of this literature showing the incomplete study designs along with convincing foundational new data and publications supporting Pg OMVs as the major delivery mechanism will be provided.