Interaction between genetic factors, Porphyromonas gingivalis and microglia to promote Alzheimer’s disease

Figures & data

Table 1. Potential mechanisms for microglia affection by Porphyromonas gingivalis (P.g.).

Factor	Mechanism	Ref
Gingipains	Inhibitors of gingipains are being tested for reducing p-Tau toxicity in man	[4]
	Persistent expression of gingipains in P.g.infected neu-rons gave AD-like neurodegeneration	[8]
	Secreted gingipains from P.g. induced microglia migration	[11]
	Inhibitors of Rgp and Kgp suppressed P.g.induced micro-glia migration	[10]
Matrix metallo-proteinases (MMPs)
	P.g. can induce synthesis of MMPs in host tissues and cells	[16]
	P.g. may contribute to the brain pool of MMPs	[4,19]
Inhibitors of MMPs
(TIMPs)	P.g. inactivated TIMP-1 and TIMP-2 causing destruction of connective tissue	[20]
Clusterin gene	Clusterin is a complement cascade regulatory plasma protein. P.g. phosphorylated its ser396 in mice	[8]
CR1 gene	CR1 regulates complement cascade. P.g.causes immune subversion in relation to CR1	[52]
CD33	Belongs to an Ig-like family of receptors expressed on microglia.CR1 and is highly expressed on CD33+ cells to which P. g. binds	[57]
TREM-2 gene	Codes for a protein expressed on microglia. P.g. down-regu-lates TREM-2 expression on microglia which may accele-rate AD	[58,59]
TYR-OBP gene	Key signaling molecule for TREM-2	[64]
Complement	P.g. initiated AD inflammation involving the comple-ment cascade of ApoE^−/- brains	[25]
LPS	Initiates neuroinflammation through microglia activation	[68]
	Migroglia were ‘primed’ inducing increased responses to subsequent challenges	[68]
	When located in brains microglia can be activated by P.g. LPS	[4,76]
	P.g. causes imbalance in the M1/M2 phenotype of microglia	[78]
Leptomeningeal cells	P.g. LPS stimulated transfer of inflammatory signals from peripheral macrophages to brain-resident microglia	[83,84]
	Administration of P.g. to mice caused P.g. and its prote-ases to be detected intra- and perinuclear in microglia	[8]

Figure 1. Brain tissue showing microglia responding to infection in a mouse model and to Aβ plaque in a brain tissue section from Alzheimer’s disease.

(a) Confocal image. Brain tissue showing microglia (white arrows) following mono-P. gingivalis infection (24 weeks) from an apolipoprotein E^−/- mouse brain immunolabelled to demonstrate microglia (anti-1ba1); Blue = DAPI; Red = TRITC label for immunopositive microglia. (b) Immunohistochemistry. Double labelling of a cortical human AD brain tissue section showing activated microglia brown (anti-HLADR) demarcated by black arrows, and Aβ plaque (anti-Aβ) blue (white arrow head) to demonstrate their relationship.

Dominy SS, Lynch C, Ermini F, et al. Porphyromonas gingivalis in Alzheimer’s disease brains: evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv. 2019;5:eaaa3333.

 Web of Science ®Google Scholar

Ilievski V, Zuchowska PK, Green SJ, et al. Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice. PLoS One. 2018;13(10):e0204941.

 PubMed Web of Science ®Google Scholar

Nonaka S, Nakanishi H. Secreted gingipains from Porphyromonas gingivalis induce microglia migration through endosomal signaling by protease-activated receptor 2. Neurochem Int. 2020;104840. DOI:10.1016/j.neuint.2020.104840.

 Web of Science ®Google Scholar

Liu Y, Wu Z, Nakanishi Y, et al. Infection of microglia with Porphyromonas gingivalis promotes cell migration and an inflammatory response through the gingipain-mediated activation of protease-activated receptor-2 in mice. Sci Rep. 2017;7(1):11759. Liu Y, Wu Z, Nakanishi Y, et al. Author Correction: Infection of microglia with Porphyromonas gingivalis promotes cell migration and an inflammatory response through the gingipain-mediated activation of protease-activated receptor-2 in mice. Sci Rep. 2018; 8: 10304.

 PubMedGoogle Scholar

Irshad M, Scheres N, Anssari Moin D, et al. Cytokine and matrix metalloproteinase expression in fibroblasts from peri-implantitis lesions in response to viable Porphyromonas gingivalis. J Periodontal Res. 2013;48(5):647–656.

 PubMed Web of Science ®Google Scholar

Poole S, Singhrao SK, Kesavalu L, et al. Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer’s disease brain tissue. J Alzheimers Dis. 2013;36(4):665–677.

 PubMed Web of Science ®Google Scholar

Sato Y, Kishi J, Suzuki K, et al. Sonic extracts from a bacterium related to periapical disease activate gelatinase A and inactivate tissue inhibitor of metalloproteinases TIMP-1 and TIMP-2. Int Endod J. 2009;42(12):1104–1111.

 Web of Science ®Google Scholar

Hajischengallis G, Liang S, Payne MA, et al. Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement. Cell Host Microbe. 2011;10(5):497–506.

 Web of Science ®Google Scholar

Repik A, Pincus SE, Ghiran I, et al. A transgenic mouse model for studying the clearance of blood-borne pathogens via human complement receptor 1 (CR1). Clin Experiment Immunol. 2005;140(2):230–240.

 Web of Science ®Google Scholar

Neumann H, Daly MJ. Variant TREM2 as risk factor for Alzheimer’s disease. N Engl J Med. 2013;368(2):182–184.

 Web of Science ®Google Scholar

Jiang T, Yu J-T, Zhu X-C, et al. TREM2 in Alzheimer’s disease. Mol Neurobiol. 2013;48(1):180–185.

 PubMed Web of Science ®Google Scholar

Zhang B, Gaiteri C, Bodea LG, et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell. 2013;153:707–720.

 PubMed Web of Science ®Google Scholar

Poole S, Singhrao SK, Chukkapalli S, et al. Active invasion of Porphyromonas gingivalis and infection-induced complement activation in ApoE−/- mice brains. J Alzheimers Dis. 2015;43(1):67–80.

 PubMed Web of Science ®Google Scholar

Cunningham C, Wilcockson DC, Campion S, et al. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci. 2005;25(40):9275–9284.

 PubMed Web of Science ®Google Scholar

Memedovski Z, Czerwonka E, Han J, et al. Classical and alternative activation of rat microglia treated with ultrapure Porphyromonas gingivalis lipopolysaccharide in vitro. Toxins (Basel). 2020;12(5):333.

 Web of Science ®Google Scholar

Yu S, Ding L, Liang D, et al. Porphyromonas gingivalis inhibits M2 activation of macrophages by suppressing α-ketoglutarate production in mice. Mol Oral Microbiol. 2018;33(5):388–395.

 Web of Science ®Google Scholar

Liu Y, Wu Z, Zhang X, et al. Leptomeningeal cells transduce peripheral macrophages inflammatory signal to microglia in response to Porphyromonas gingivalis LPS. Mediators Inflammation. 2013;2013:407562.

 PubMed Web of Science ®Google Scholar

Wu Z, Nakanishi H. Connection between periodontitis and Alzheimer’s disease: possible roles of microglia and leptomeningeal cells. J Pharmacol Sci. 2014;126(1):8–13.

 PubMed Web of Science ®Google Scholar