Are Porphyromonas gingivalis Outer Membrane Vesicles Microbullets for Sporadic Alzheimer's Disease Manifestation?

Abstract

Our research into Alzheimer's disease (AD) focuses on the oral cavity and the brain, from which key evaluations of prospective and retrospective population-based data have shown that chronic periodontal disease existing for ten-years or over doubles the risk for the sporadic form of AD. Furthermore, Porphyromonas gingivalis (P. gingivalis) mono-infections in established periodontal lesions, or introducing its lipopolysachharide (LPS), as demonstrated in in vivo studies, show hallmark pathology inclusive of extracellular amyloid plaques and phospho-tau bound neurofibrillary tangles with AD-like phenotype. Other studies have shown that if periodontitis remains untreated in human AD patients, cognitive decline ensues. This is a bi-directional relationship meaning that the converse is also true; treating periodontal disease in AD patients improves memory. Bacterial cultures and established oral biofilms generate vast numbers of microvesicles and P. gingivalis outer membrane vesicles encase key virulence factors (LPS, gingipains, capsule, fimbriae) as though they are complete destructive "microbullets" when shed in the host. This provides P. gingivalis additional arsenal to manipulate its entry into disparate organs, hijack phagocytosis, destroy tissues, and affect complement related genes while transducing the onset of proinflammatory signaling cascades. The resulting inflammatory mediators may be the cause of disease defining lesions and cognitive decline typical of clinical AD.

Keywords: Alzheimer’s disease; P. gingivalis; microbullets; outer membrane vesicles; periodontitis.

Fig.1

Schematic summary illustrates the extrinsic sources of inflammation involving periodontal and vascular pathologies to the brain including the local inflammation in each co-morbid state. a) Periodontitis: Body’s response is to initiate the innate immune defense mechanism. This results in recruitment of polymorphonuclear neutrophils (PMNs), which P. gingivalis uses as Trojan horses to enter below the gingivae. The host initiates P. gingivalis mediated inflammatory signaling pathways (lipopolysaccharide (LPS) receptor (CD14), and the highly conserved toll like receptors 2 and 4 (TLRs), nuclear factor κB (NF-κB), and the IL-1 receptor-activated kinase 1 (IRAK1). The bacterial proteases and LPS from the outer membrane vesicles (OMVs) directly damage connective tissues (elastin, fibrinogen, collagen) and the host cells also react by up regulating matrix metalloproteinases (MMPs) causing severe loss of host tissues. The humoral and adaptive immune response indicated by B-cells, plasma cells and T-cells (Th2) trigger immunoglobulin release and multiple cytokines (TNF-α, IL-1, IL-6, IL-8) and complement activation. The secretion of PGE2 and other cytokines NF-κB, receptor activator of NF-κB ligand (RANKL/RANK), macrophage colony stimulating factor (M-CSF) and osteoprotegrin (OPG) affect the alveolar bone homeostasis such that osteoclasts (OCs) begin bone resorption. b) Bacteraemias: PMNs and macrophages (MΦs) augment the expression of scavenger receptors in response to either local and/or extrinsic sources of inflammatory mediators and oral bacteraemia. Lipid-laden cells secrete proinflammatory cytokines, with recruitment of Th1/2 and MΦs within the atheromatous plaque where P. gingivalis lurks. Direct innate immune responses and additional cytokines and growth factors cause migration of smooth muscle cells (SMCs) and complement activation. c) Brain: The extrinsic factors from both periodontal disease and the vascular atheroma cause the initial trigger from systemic inflammation to affect the brain. This then leads to intracerebral inflammation (glia activated by P. gingivalis LPS from OMVs) leading to complement activation and emergence of hallmark proteins (Aβ and NFTs) that define Alzheimer’s disease.

Fig.2

Schematic to show oral pathogen/endotoxin entry direct and/or indirect into the brain following bacteraemias. A) Attenuated P. gingivalis/LPS within the systemic circulation can gain access to the brain via transport across the blood-brain barrier (BBB). Once organisms are present in the ventricular cerebrospinal fluid (CSF), they can potentially invade the subarachnoid space. From the CSF, bacteria cross the ependymal epithelial cell layer lining the ventricle wall for entry into the brain parenchyma. A1 represents an infection encountered in advanced age and A2 in younger age. Bacteria within the systemic circulation can gain access to the perivascular spaces, which in turn connect with the subarachnoid space. The CSF connects to and communicates with the lateral and third ventricles providing access for pathogens to all parts of the CNS. B) Endotoxin transfer directly into the brain via circumventricular organs and indirectly via antigen presentation: The meninges have a well-developed population of dendritic cells and meningeal cells that communicate through lymphatic vessels with the adaptive immune system located in the systemic lymph nodes. Dendritic cells in blood vessels of the choroid plexus and the meninges/leptomeninges house cells expressing the mannose receptor, lipopolysaccharide (LPS) receptor (CD14), and the highly conserved toll like receptors 2 and 4 (TLR 2 and 4).