Intracerebral but Not Peripheral Infection of Live Porphyromonas gingivalis Exacerbates Alzheimer’s Disease Like Amyloid Pathology in APP-TgCRND8 Mice

Abstract

The impact of oral microbial dysbiosis on Alzheimer’s disease (AD) remains controversial. Building off recent studies reporting that various microbes might directly seed or promote amyloid β (Aβ) deposition, we evaluated the effects of periodontal bacteria (Porphyromonas gingivalis, Treponema denticola) and supragingival commensal (Streptococcus gordonii) oral bacterial infection in the APP-transgenic CRND8 (Tg) mice model of AD. We tracked bacterial colonization and dissemination, and monitored effects on gliosis and amyloid deposition. Chronic oral infection did not accelerate Aβ deposition in Tg mice but did induce alveolar bone resorption, IgG immune response, and an intracerebral astrogliosis (GFAP: glial fibrillary acidic protein). In contrast, intracerebral inoculation of live but not heat-killed P. gingivalis increased Aβ deposition and Iba-1 (ionized calcium-binding adaptor-1) microgliosis after 8 weeks of bacterial infection but not at 4 days. These data show that there may be differential effects of infectious microbes on glial activation and amyloid deposition depending on the species and route of inoculation, and thereby provide an important framework for future studies. Indeed, these studies demonstrate marked effects on amyloid β deposition only in a fairly non-physiologic setting where live bacteria is injected directly into the brain.

Global Noncoding microRNA Profiling in Mice Infected with Partial Human Mouth Microbes (PAHMM) Using an Ecological Time-Sequential Polybacterial Periodontal Infection (ETSPPI) Model Reveals Sex-Specific Differential microRNA Expression

“…Further data indicate that S. gordonii has a highly invasive potential to disseminate from gingival epithelial tissues to distal organs such as the lungs, kidney, and liver and to gain access to systemic circulation. We also observed a similar dissemination pattern of S. gordonii to the heart, lungs, spleen, and kidneys in both APP-transgenic CRND8 (Tg) and wild-type nontransgenic (ntg) mice [30]. In addition, S. gordonii is not only a commensal supragingival bacterium but also an opportunistic pathogen, and it can enter the bloodstream, leading to endocarditis [31].…”

“…The oral spirochete T. denticola ATCC 35405 strain was grown in GM-1 broth [2,21], and T. forsythia ATCC 49307 was grown in TSB broth supplemented with N-acetyl muramic acid (5 mg/mL) and hemin (1 mg/mL) [21,63]. All the bacteria were cultured and harvested in a Coy anaerobic chamber at 37 • C for 2 to 3 days as previously described [24,25,30,63]. P. gingivalis, S. gordonii, and F. nucleatum were harvested from the media plates by using a sterile cotton tip applicator.…”

Antimicrobial Peptides Active in In Vitro Models of Endodontic Bacterial Infections Modulate Inflammation in Human Cardiac Fibroblasts

“…Chronic disease also triggers sustained release of proinflammatory mediators that are essential to the development of inflammation [ 3 , 4 ] and can eventually have detrimental effects on distant organs. Many epidemiological studies suggest that periodontitis is associated with atherosclerotic cardiovascular disease [ 5 , 6 , 7 ]. Bacteria enter the systemic circulation, stimulating atherogenesis through endothelial damage and inflammation, as shown by the fact that experimental bacteremia induced by P. gingivalis in animals leads to atherogenesis [ 8 ].…”