GSK3β is involved in promoting Alzheimer’s disease pathologies following chronic systemic exposure to Porphyromonas gingivalis lipopolysaccharide in amyloid precursor proteinNL-F/NL-F knock-in mice

2021 ◽  
Author(s):  
Muzhou Jiang ◽  
Xinwen Zhang ◽  
Xu Yan ◽  
Shinsuke Mizutani ◽  
Haruhiko Kashiwazaki ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Porphyromonas Gingivalis ◽  
Systemic Exposure ◽  
Porphyromonas Gingivalis Lipopolysaccharide

scholarly journals Systemic Exposure to Lipopolysaccharide from Porphyromonas gingivalis Induces Bone Loss-Correlated Alzheimer’s Disease-Like Pathologies in Middle-Aged Mice

2020 ◽  
Vol 78 (1) ◽  
pp. 61-74
Author(s):  
Yebo Gu ◽  
Zhou Wu ◽  
Fan Zeng ◽  
Muzhou Jiang ◽  
Jessica L. Teeling ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Bone Loss ◽  
Porphyromonas Gingivalis ◽  
Specific Inhibitor ◽  
Systemic Exposure ◽  
Memory Decline ◽  
Periodontal Bacteria ◽  
Pre Treatment ◽  
Total Tissue

Background: Alzheimer’s disease (AD) and bone loss are clinically exacerbated. However, the mechanism of exacerbation remains understood. Objective: We tested our hypothesis that periodontitis is involved in the exacerbation, contributing to AD pathologies. Methods: The bone, memory, and inflammation in bone and brain were examined in 12-month-old mice after systemic exposure to lipopolysaccharide from Porphyromonas gingivalis (P gLPS) for 3 consecutive weeks. Results: Compared with control mice, bone loss in tibia (26% decrease) and memory decline (47% decrease) were induced in mice with a positive correlation after exposure to P gLPS (r = 0.7378, p = 0.0011). The IL-6 and IL-17 expression in tibia was negatively correlated with the bone volume/total tissue volume (r = –0.6619, p = 0.0052; r = –0.7129, p = 0.0019), while that in the cortex was negatively correlated with the memory test latency (r = –0.7198, p = 0.0017; p = 0.0351, r = –0.5291). Furthermore, the IL-17 expression in microglia was positively correlated with Aβ42 accumulation in neurons (r = 0.8635, p < 0.0001). In cultured MG6 microglia, the P gLPS-increased IL-6 expression was inhibited by a PI3K-specific inhibitor (68% decrease), and that of IL-17 was inhibited by IL-6 antibody (41% decrease). In cultured N2a neurons, conditioned medium from P gLPS-stimulated microglia (MCM) but not P gLPS increased the productions of AβPP, CatB, and Aβ42, which were significantly inhibited by pre-treatment with IL-17 antibody (67%, 51%, and 41% decrease). Conclusion: These findings demonstrated that chronic systemic exposure to P gLPS simultaneously induces inflammation-dependent bone loss and AD-like pathologies by elevating IL-6 and IL-17 from middle age, suggesting that periodontal bacteria induce exacerbation of bone loss and memory decline, resulting in AD progression.

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

2020 ◽  
Vol 11 ◽  
Author(s):  
Chiaki Yamada ◽  
Juliet Akkaoui ◽  
Anny Ho ◽  
Carolina Duarte ◽  
Richard Deth ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Porphyromonas Gingivalis ◽  
Virulence Factors ◽  
Potential Role ◽  
Sirtuin 1 ◽  
Periodontal Pathogen ◽  
Secretory Phenotype ◽  
Aβ42 Peptide

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.

scholarly journals Characterization of Human Genes Modulated by Porphyromonas gingivalis Highlights the Ribosome, Hypothalamus, and Cholinergic Neurons

2021 ◽  
Vol 12 ◽  
Author(s):  
Sejal Patel ◽  
Derek Howard ◽  
Nityananda Chowdhury ◽  
Casey Derieux ◽  
Bridgette Wellslager ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Porphyromonas Gingivalis ◽  
Protein Targeting ◽  
Expression Patterns ◽  
Cholinergic Neurons ◽  
Functional Enrichment ◽  
Differentially Expressed ◽  
Human Genes ◽  
Lysine Residues

Porphyromonas gingivalis, a bacterium associated with periodontal disease, is a suspected cause of Alzheimer’s disease. This bacterium is reliant on gingipain proteases, which cleave host proteins after arginine and lysine residues. To characterize gingipain susceptibility, we performed enrichment analyses of arginine and lysine proportion proteome-wide. Genes differentially expressed in brain samples with detected P. gingivalis reads were also examined. Genes from these analyses were tested for functional enrichment and specific neuroanatomical expression patterns. Proteins in the SRP-dependent cotranslational protein targeting to membrane pathway were enriched for these residues and previously associated with periodontal and Alzheimer’s disease. These ribosomal genes are up-regulated in prefrontal cortex samples with detected P. gingivalis sequences. Other differentially expressed genes have been previously associated with dementia (ITM2B, MAPT, ZNF267, and DHX37). For an anatomical perspective, we characterized the expression of the P. gingivalis associated genes in the mouse and human brain. This analysis highlighted the hypothalamus, cholinergic neurons, and the basal forebrain. Our results suggest markers of neural P. gingivalis infection and link the cholinergic and gingipain hypotheses of Alzheimer’s disease.

scholarly journals Preclinical validation of a potent γ-secretase modulator for Alzheimer’s disease prevention

2021 ◽  
Vol 218 (4) ◽  
Author(s):  
Kevin D. Rynearson ◽  
Moorthi Ponnusamy ◽  
Olga Prikhodko ◽  
Yuhuan Xie ◽  
Can Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Safety Margin ◽  
Systemic Exposure ◽  
Secretase Activity ◽  
Adverse Effect Level ◽  
Prevention Studies ◽  
Effect Level ◽  
Multiple Species ◽  
Dose Dependent

A potent γ-secretase modulator (GSM) has been developed to circumvent problems associated with γ-secretase inhibitors (GSIs) and to potentially enable use in primary prevention of early-onset familial Alzheimer’s disease (EOFAD). Unlike GSIs, GSMs do not inhibit γ-secretase activity but rather allosterically modulate γ-secretase, reducing the net production of Aβ42 and to a lesser extent Aβ40, while concomitantly augmenting production of Aβ38 and Aβ37. This GSM demonstrated robust time- and dose-dependent efficacy in acute, subchronic, and chronic studies across multiple species, including primary and secondary prevention studies in a transgenic mouse model. The GSM displayed a &gt;40-fold safety margin in rats based on a comparison of the systemic exposure (AUC) at the no observed adverse effect level (NOAEL) to the 50% effective AUC or AUCeffective, the systemic exposure required for reducing levels of Aβ42 in rat brain by 50%.

scholarly journals Evidence on Integrating Pharmacokinetics to Find Truly Therapeutic Agent for Alzheimer’s Disease: Comparative Pharmacokinetics and Disposition Kinetics Profiles of Stereoisomers Isorhynchophylline and Rhynchophylline in Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Chunyuan Zhang ◽  
Xu Wu ◽  
Yanfang Xian ◽  
Lin Zhu ◽  
Ge Lin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Oral Administration ◽  
Therapeutic Agent ◽  
Therapeutic Potential ◽  
Systemic Exposure ◽  
The Body ◽  
Chinese Medicinal Herb ◽  
Disposition Kinetics ◽  
The Brain

Isorhynchophylline (IRN) and rhynchophylline (RN), a pair of stereoisomers, are tetracyclic oxindole alkaloids isolated from Uncaria rhynchophylla, a commonly used Chinese medicinal herb. These two compounds have drawn extensive attention due to their potent neuroprotective effects with promising therapeutic potential for the treatment of Alzheimer’s disease (AD). However, IRN and RN can interconvert into each other in vivo after oral administration. The present study aimed to elucidate the pharmacokinetic profiles and disposition kinetics of the administered and generated stereoisomers in the brain and cerebrospinal fluid (CSF) after oral administration of equal dose of IRN or RN to rats. Our study demonstrated that after oral administration, RN showed significantly higher systemic exposure (6.5 folds of IRN, p < 0.001) and disposition in the brain (2.5 folds of IRN, p < 0.01) and CSF (3 folds of IRN, p < 0.001) than IRN. The results indicated that interconversion between IRN and RN occurred. Notably, regardless of the orally administered IRN or RN, RN would always be one of the major or predominant forms present in the body. Our results provided sound evidence supporting further development of RN as a potential therapeutic agent for the treatment of AD. Moreover, the present study sets a solid example that integrating pharmacokinetics is crucial to identify the truly therapeutic agent.

scholarly journals Alzheimer’s Disease-Like Pathology Triggered by Porphyromonas gingivalis in Wild Type Rats Is Serotype Dependent

2020 ◽  
Vol 11 ◽  
Author(s):  
Jaime Díaz-Zúñiga ◽  
Jamileth More ◽  
Samanta Melgar-Rodríguez ◽  
Matías Jiménez-Unión ◽  
Francisca Villalobos-Orchard ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Porphyromonas Gingivalis ◽  
Wild Type
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