Porphyromonas gingivalis is a Strong Risk Factor for Alzheimer's Disease

Abstract

Porphyromonas gingivalis (P. gingivalis) is one of the several important bacterial pathogens associated with the sporadic Alzheimer's disease (AD). Different serotypes are either capsulated or are non-capsulated. It has been demonstrated that P. gingivalis (non-capsulated) can reproduce the neurodegenerative AD-like changes in vitro, and a capsular P. gingivalis (strain W83) could reproduce the cardinal hallmark lesions of AD in a wild-type mouse model. All P. gingivalis forms express proteolytically active proteases that enable cleavage of the amyloid-β protin precursor (AβPP) and tau resulting in the formation of amyloid-β and neurofibrillary tangles. Tau is an established substrate for gingipains, which can cleave tau into various peptides. Some of the P. gingivalis fragmented tau protein peptides contain "VQIINK" and "VQIVYK" hexapeptide motifs which map to the flanking regions of the microtubule binding domains and are also found in paired helical filaments that form NFTs. P. gingivalis can induce peripheral inflammation in periodontitis and can also initiate signaling pathways that activate kinases, which in turn, phosphorylate neuronal tau. Periodontal disease related inflammation has metabolic implications for an individual's peripheral and brain health as patients suffering from generalized periodontitis often have related co-morbidities and are "at risk" of developing AD. The aim here is to discuss the role of P. gingivalis behind such associations with the backdrop of huge efforts to test P. gingivalis virulence factors clinically (GAIN Trial: Phase 2/3 Study of COR388 in Subjects with AD) with inhibitors, which may lead to an intervention by reducing the pathogenic bacterial load.

Keywords: Alzheimer’s disease; Porphyromonas gingivalis; gingipains; periodontal disease.

Fig. 1

The keystone periodontal pathogen, P. gingivalis (P.g), can enter the bloodstream during episodes of transient bacteremia and gain access to the brain via multiple routes including a leaky blood-brain barrier. The microbial invasion triggers the cerebral immune response resulting in neuroinflammation and in the formation of the two diagnostic lesions of AD. Periodontitis can exert its influence indirectly by sustaining peripheral inflammation (blue dotted arrow). This can affect glial cells by priming them into a pro-inflammatory phenotype. In addition, this could also overload and overwhelm the clearing of toxic neuropeptides from the central nervous system (CNS). The potential causal relationship of periodontitis and AD is further supported by the shared risk factors.

Fig. 2

Schematic of tau protein and domain organization to help understand the position of peptides in Table 1 and the 1–4 microtubule binding domains of Tau to microtubules.