Potential Role of Phosphoglycerol Dihydroceramide Produced by Periodontal Pathogen Porphyromonas gingivalis in the Pathogenesis of Alzheimer’s Disease

Abstract

BackgroundAmong different types of sphingolipids produced by human cells, the possible engagement of ceramide species in the pathogenesis of Alzheimer’s disease (AD) has attracted recent attention. While ceramides are primarily generated by de novo synthesis in mammalian cells, only a limited number of bacterial species, produce ceramides, including phosphoglycerol dihydroceramide (PGDHC) that is produced by the key periodontal pathogen Porphyromonas gingivalis. Emerging evidence indicates that virulence factors produced by P. gingivalis, such as lipopolysaccharide and gingipain, may be engaged in the initiation and/or progression of AD. However, the potential role of PGDHC in the pathogenesis of AD remains unknown. Therefore, the aim of this study was to evaluate the influence of PGDHC on hallmark findings in AD.Material and MethodsCHO-7WD10 and SH-SY-5Y cells were exposed to PGDHC and lipopolysaccharide (LPS) isolated from P. gingivalis. Soluble Aβ42 peptide, amyloid precursor protein (APP), phosphorylated tau and senescence-associated secretory phenotype (SASP) factors were quantified using ELISA and Western blot assays. ResultsOur results indicate that P. gingivalis (Pg)-derived PGDHC, but not Pg-LPS, upregulated secretion of soluble Aβ42 peptide and expression of APP in CHO-7WD10 cells. Furthermore, hyperphosphorylation of tau protein was observed in SH-SY-5Y cells in response to PGDHC lipid. In contrast, Pg-LPS had little, or no significant effect on the tau phosphorylation induced in SH-SY-5Y cells. However, both PGDHC and Pg-LPS contributed to the senescence of SH-SY5Y cells as indicated by the production of senescence-associated secretory phenotype (SASP) markers, including beta-galactosidase, cathepsin B (CtsB), and pro-inflammatory cytokines TNF-α, and IL-6. Additionally, PGDHC diminished expression of the senescence-protection marker sirtuin-1 in SH-SY-5Y cells.ConclusionsAltogether, our results indicate that P. gingivalis-derived PGDHC ceramide promotes amyloidogenesis and hyperphosphorylation, as well as the production of SASP factors. Thus, PGDHC may represent a novel class of bacterial-derived virulence factors for AD associated with periodontitis.

Evidence and Therapeutic Perspectives in the Relationship between the Oral Microbiome and Alzheimer’s Disease: A Systematic Review

“…According to the study of Dominy et al, on mice, the presence of P. gingivalis and gingipaïn in the brain plays a central role in the pathogenesis of AD [ 39 ]. In vitro, Yamada et al demonstrated that exposure to phosphoglycerol dihydroceramide produced by P. gingivalis (PGDHC) increased Aβ peptide secretion in a dose-dependent manner in the Chinese hamster ovary-7WD10 cells, stably expressing wild-type human amyloid precursor protein (APP) and induced specific phosphorylation of Tau protein in a dose-dependent manner in human neuroblastoma cells [ 40 ]. In rats, Zhang et al showed a significant elevation of Aβ1-40 peptide levels in the cerebral cortex of AD rats with periodontitis compared to AD rats without it [ 41 ].…”

“…While neuroimmune interactions are essential to brain function [ 45 ], chronic inflammation appears to be a key factor in the pathophysiology and clinical progression of AD [ 46 ]. In vitro, Yamada et al showed that exposure of human neuroblastoma cells to PGDHC or Pg-LPS increased expression of the senescence-associated secretory phenotype involving β-galactosidase, cathepsin B, cysteine, and pro-inflammatory cytokines TNF-α and IL-6 [ 40 ].…”

Bioinformatics analysis of gene expression profile and functional analysis in periodontitis and Parkinson’s disease

“…Moreover, phosphoglycerol dihydroceramide (produced by the periodontal pathogen Porphyromonas gingivalis) promotes amyloidogenesis and hyperphosphorylation, and promotes the pathogenesis of AD (Yamada et al, 2020).…”

Crosstalk between dihydroceramides produced by Porphyromonas gingivalis and host lysosomal cathepsin B in the promotion of osteoclastogenesis

“…While it has been demonstrated that intracellular host ceramides increase LPM and directly activate CatB in the cytoplasm of myeloid cells, 23 there is no clear evidence for the association between CatB activity and PGDHC in osteoclastogenesis and osteolysis. However, we recently demonstrated that PGDHC significantly elevates the expression of CatB in neurons, in vitro 24 . Thus, these observations raise an intriguing question of whether PGDHC plays a role in CatB release into the cytosol leading to dramatically elevated RANKL‐induced osteoclastogenesis.…”

“…However, we recently demonstrated that PGDHC significantly elevates the expression of CatB in neurons, in vitro . 24 Thus, these observations raise an intriguing question of whether PGDHC plays a role in CatB release into the cytosol leading to dramatically elevated RANKL‐induced osteoclastogenesis.…”