SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia

The emergence of SARS‐CoV‐2 has resulted in a global pandemic. In addition to respiratory complications as a result of SARS‐CoV‐2 illness, accumulating evidence suggests that neurological and neuropsychiatric symptoms are associated with the disease caused by the virus. In this study, we investigated the effects of the SARS‐CoV‐2 spike glycoprotein S1 stimulation on neuroinflammation in BV-2 microglia. Analyses of culture supernatants revealed an increase in the production of TNFα, IL-6, IL-1β and iNOS/NO. SARS‐CoV‐2 spike glycoprotein S1 increased protein expressions of phospho-p65 and phospho-IκB, as well as enhancing DNA binding and transcriptional activity of NF-κB. Pro-inflammatory effects of the glycoprotein effects were reduced in the presence of BAY11-7082 (1 μM). The presence of SARS‐CoV‐2 spike glycoprotein S1 in BV-2 microglia increased the protein expression of NLRP3, as well as caspase-1 activity. However, pre-treatment with CRID3 (1 μM) or BAY11-7082 (1 μM) resulted in the inhibition of NLRP3 inflammasome/caspase-1. It was also observed that CRID3 attenuated SARS‐CoV‐2 spike glycoprotein S1-induced increase in IL-1β production. Increased protein expression of p38 MAPK was observed in BV-2 microglia stimulated with the spike glycoprotein S1, and was reduced in the presence of SKF 86002. These results have provided the first evidence demonstrating SARS-CoV-2 spike S1 glycoprotein-induced neuroinflammation in BV-2 microglia. We propose that promotion of neuroinflammation by this glycoprotein is mediated through activation of NF-κB, NLRP3 inflammasome and p38 MAPK. These results are significant because of their relevance to our understanding of neurological and neuropsychiatric symptoms observed in patients infected with SARS-CoV-2.

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Artificially Cultivated Ophiocordyceps sinensis Alleviates Diabetic Nephropathy and Its Podocyte Injury via Inhibiting P2X7R Expression and NLRP3 Inflammasome Activation

Journal of Diabetes Research ◽

10.1155/2018/1390418 ◽

2018 ◽

Vol 2018 ◽

pp. 1-16 ◽

Cited By ~ 3

Author(s):

Chao Wang ◽

Xiao-xia Hou ◽

Hong-liang Rui ◽

Li-jing Li ◽

Jing Zhao ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Protein Expression ◽

Nlrp3 Inflammasome ◽

Kidney Tissue ◽

Therapeutic Effects ◽

Low Grade ◽

Podocyte Injury ◽

Ophiocordyceps Sinensis ◽

Caspase 1 ◽

Mrna And Protein Expression

Background/Aims. It is known that chronic low-grade inflammation contributes to the initiation and development of both diabetes and diabetic nephropathy (DN), so we designed this study to investigate the role of P2X7R and NLRP3 inflammasome in DN pathogenesis and the antagonistic effects of artificially cultivated Ophiocordyceps sinensis (ACOS). Methods. A rat model of DN caused by high-fat-diet feeding and low-dose streptozotocin injection and a mouse podocyte injury model induced by high-glucose (HG) stimulation were established, and the intervention effects of ACOS on them were observed. The biological parameters of serum and urine and the pathological manifestations of kidney tissue were examined. The expression of mRNA and protein of P2X7R and NLRP3 inflammasome (NLRP3, ASC, and caspase-1) and downstream effectors (IL-1β and IL-18), as well as podocyte-associated molecules, was determined by real-time quantitative PCR and Western blot assay, respectively. Results. The DN rats showed to have developed insulin resistance, elevated fasting blood glucose, increased urinary protein excretion, and serum creatinine level as well as corresponding glomerular pathological alterations including podocyte damages. ACOS significantly antagonized the above changes. The experiments in vivo and in vitro both displayed that the mRNA and protein expression of P2X7R, NLRP3, ASC, caspase1 (procaspase-1 mRNA in the gene level and active caspase-1 subunit P10 in the protein level), IL-1β, and IL-18 was significantly upregulated and the mRNA and protein expression of podocyte-associated molecules was significantly changed (downregulation of nephrin, podocin, and WT-1 expression and upregulation of desmin expression) indicating podocyte injury in the kidney tissue of DN rats and in the HG-stressed mouse podocytes, respectively. ACOS also significantly antagonized all the above changes. Conclusion. Our research work suggests that P2X7R and NLRP3 inflammasome are involved in the pathogenesis of DN, and ACOS can effectively inhibit the high expression of P2X7R and the activation of NLRP3 inflammasome, which may contribute to the therapeutic effects of Ophiocordyceps sinensis.

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3β,23-Dihydroxy-12-ene-28-ursolic Acid Isolated from Cyclocarya paliurus Alleviates NLRP3 Inflammasome-Mediated Gout via PI3K-AKT-mTOR-Dependent Autophagy

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2022/5541232 ◽

2022 ◽

Vol 2022 ◽

pp. 1-15

Author(s):

Dongxiao Lou ◽

Xiaogai Zhang ◽

Cuihua Jiang ◽

Fang Zhang ◽

Chao Xu ◽

...

Keyword(s):

Protein Expression ◽

Ursolic Acid ◽

Nlrp3 Inflammasome ◽

Soft Tissues ◽

Underlying Mechanism ◽

Inhibitory Effect ◽

Expression Level ◽

Expression Ratio ◽

Cyclocarya Paliurus ◽

Caspase 1

Gout is regarded as a painful inflammatory arthritis induced by the deposition of monosodium urate crystals in joints and soft tissues. Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-mediated IL-1β production plays a crucial role in the pathological process of gout. Cyclocarya paliurus (CP) tea was found to have an effect on reducing the blood uric acid level of people with hyperuricemia and gout. However, its medicinal ingredients and mechanism for the treatment of gout are still unclear. Thus, this study was designed to investigate the effects of the active triterpenoids isolated from C. paliurus on gout and explore the underlying mechanism. The results showed that compound 2 (3β,23-dihydroxy-12-ene-28-ursolic acid) from C. paliurus significantly decreased the protein expression of IL-1β, caspase-1, pro-IL-1β, pro-caspase-1, and NLRP3. Furthermore, the production of ROS in the intracellular was reduced after compound 2 treatment. However, ROS agonist rotenone remarkably reversed the inhibitory effect of compound 2 on the protein expression of NLRP3 inflammasome. Additionally, the expression level of LC3 and the ratio of LC3II/LC3I were increased, but the expression level of p62 was suppressed by compound 2 whereas an autophagy inhibitor 3-methyladenine (3-MA) significantly abolished the inhibitory effects of compound 2 on the generation of ROS and the protein expression of NLRP3 inflammasome. Moreover, compound 2 could ameliorate the expression ratio of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR. Interestingly, mTOR activator MHY-1485 could block the promotion effect of compound 2 on autophagy regulation and inhibitory effect of compound 2 on induction of ROS and IL-1β. In conclusion, these findings suggested that compound 2 may effectively improve NLRP3 inflammasome-mediated gout via PI3K-AKT-mTOR-dependent autophagy and could be further investigated as a potential agent against gout.

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Effects of Sulfonylureas on Periodontopathic Bacteria-Induced Inflammation

Journal of Dental Research ◽

10.1177/0022034520913250 ◽

2020 ◽

Vol 99 (7) ◽

pp. 830-838 ◽

Cited By ~ 1

Author(s):

Y. Kawahara ◽

T. Kaneko ◽

Y. Yoshinaga ◽

Y. Arita ◽

K. Nakamura ◽

...

Keyword(s):

Cell Death ◽

Nlrp3 Inflammasome ◽

Alveolar Bone ◽

Periodontal Diseases ◽

Human Monocyte ◽

Periodontal Pathogen ◽

Enzyme Linked Immunosorbent Assay ◽

Periodontopathic Bacteria ◽

Caspase 1 ◽

Culture Supernatants

Interleukin-1β (IL-1β) is an inflammatory cytokine produced by monocytes/macrophages and is closely associated with periodontal diseases. The NLRP3 inflammasome is involved in IL-1β activation through pro–IL-1β processing and pyroptotic cell death in bacterial infection. Recently, glyburide, a hypoglycemic sulfonylurea, has been reported to reduce IL-1β activation by suppressing activation of the NLRP3 inflammasome. Therefore, we evaluated the possibility of targeting the NLRP3 inflammasome pathway by glyburide to suppress periodontal pathogen-induced inflammation. THP-1 cells (a human monocyte cell line) were differentiated to macrophage-like cells by treatment with phorbol 12-myristate 13-acetate and stimulated by periodontopathic bacteria, Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, or Fusobacterium nucleatum, in the presence of glyburide. IL-1β and caspase-1 expression in the cells and culture supernatants were analyzed by Western blotting and enzyme-linked immunosorbent assay, and cell death was analyzed by lactate dehydrogenase assay. Stimulation of THP-1 macrophage-like cells with every periodontopathic bacteria induced IL-1β secretion without cell death, which was suppressed by the NLRP3 inhibitor, MCC950, and caspase-1 inhibitor, z-YVAD-FMK. Glyburide treatment suppressed IL-1β expression in culture supernatants and enhanced intracellular IL-1β expression, suggesting that glyburide may have inhibited IL-1β secretion. Subsequently, a periodontitis rat model was generated by injecting periodontal bacteria into the gingiva, which was analyzed histologically. Oral administration of glyburide significantly suppressed the infiltration of inflammatory cells and the number of osteoclasts in the alveolar bone compared with the control. In addition to glyburide, glimepiride was shown to suppress the release of IL-1β from THP-1 macrophage-like cells, whereas other sulfonylureas (tolbutamide and gliclazide) or other hypoglycemic drugs belonging to the biguanide family, such as metformin, failed to suppress IL-1β release. Our results suggest that pharmacological targeting of the NLRP3 pathway may be a strategy for suppressing periodontal diseases.

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Exaggerated cytokine production in human peripheral blood mononuclear cells by recombinant SARS-CoV-2 spike glycoprotein S1 and its inhibition by dexamethasone

10.1101/2021.02.03.429536 ◽

2021 ◽

Author(s):

Olumayokun A Olajide ◽

Victoria U Iwuanyanwu ◽

Izabela Lepiarz-Raba ◽

Alaa A Al-Hindawi

Keyword(s):

P38 Mapk ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Human Peripheral Blood ◽

Significant Inhibition ◽

Spike Glycoprotein ◽

Peripheral Blood Mononuclear ◽

Blood Mononuclear Cells ◽

Pre Treatment

AbstractAn understanding of the pathological inflammatory mechanisms involved in SARS-CoV-2 virus infection is necessary in order to discover new molecular pharmacological targets for SARS-CoV-2 spike glycoprotein. In this study, the effects of a recombinant SARS-CoV-2 spike glycoprotein S1 was investigated in human peripheral blood mononuclear cells (PBMCs). Stimulation with spike glycoprotein S1 (100 ng/mL) resulted in significant elevation in the production of TNFα, IL-6, IL-1β and IL-8. However, pre-treatment with dexamethasone (100 nM) caused a significant reduction in the release of these cytokines. Further experiments revealed that S1 stimulation of PBMCs increased phosphorylation of NF-κB p65 and IκBα, while increasing IκBα degradation. DNA binding of NF-κB p65 was also significantly increased following stimulation with S1. Treatment of PBMCs with dexamethasone (100 nM) or BAY11 −7082 (1 μM) resulted in inhibition of S1 -induced NF-κB activation. Activation of p38 MAPK by S1 was blocked in the presence of dexamethasone and SKF 86002. CRID3, but not dexamethasone pre-treatment produced significant inhibition of S1-induced activation of NLRP3/caspase-1. Further experiments revealed that S1-induced increase in the production of TNFα, IL-6, IL-1β and IL-8 was reduced in the presence of BAY11-7082 and SKF 86002, while CRID3 pre-treatment resulted in the reduction of IL-1β production. These results suggest that SARS-CoV-2 spike glycoprotein S1 stimulate PBMCs to release pro-inflammatory cytokines through mechanisms involving activation of NF-κB, p38 MAPK and NLRP3 inflammasome. It is proposed that clinical benefits of dexamethasone in COVID-19 is possibly due to its anti-inflammatory activity in reducing SARS-CoV-2 cytokine storm.

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Selenium ameliorates S. aureus-induced inflammation through ROS-mediated NLRP3 inflammasome in bovine mammary epithelial cells

10.21203/rs.2.23719/v1 ◽

2020 ◽

Author(s):

Chongliang Bi ◽

Shujiu Zhang ◽

He Tang ◽

Hui Li

Keyword(s):

Protein Expression ◽

Nlrp3 Inflammasome ◽

Mammary Epithelial Cells ◽

Mammary Epithelial ◽

Expression Level ◽

Bovine Mammary Epithelial Cells ◽

Caspase 1 ◽

Through Flow ◽

Anti Inflammatory ◽

Inflammatory Effect

Abstract Background Some research has indicated that selenium (Se) plays a significant role during mastitis. However the intracellular anti-inflammatory effect of Se is not fully clear. Due to the ability of Staphylococcus aureus ( S. aureus ) to internalize into host cell, in this study we explored whether Se could regulate inflammation induced by S. aureus through reactive oxygen species (ROS)-mediated NLRP3 inflammasome in bMECs. Result bMECs were treated with 8 μmol/L Na 2 SeO 3 for 12 h before infected with S. aureus for 2 h. Through flow cytometry, Western blot and qPCR analysis, ROS and NLRP3 imflammasome were detected. Result shown that the production of ROS was increased by S. aureus , Se exerted strong inhibitory effects on the production of ROS; The protein expression of NLRP3 inflammasome including NLRP3, ASC and Caspase-1 increased significantly after S. aureus infection, Se played an important role in regulating the expression of NLRP3, ASC and Caspase-1; To further investigate the anti-inflammatory effect of Se, the expression level of IL-1β associated molecule pro-IL-1β and IL-1β were detected. Result shown that the mRNA expression of IL-1β was up-regulated by S. aureus and after Se treatment the expression level of IL-1β mRNA was markedly down-regulated, meanwhile Se play a regulation effect on the protein expression of Pro-IL-1β and IL-1β. Conclusions Here we show that ROS is involved in bMECs inflammation induced by S. aureus and Se ameliorates S. aureus -induced inflammation through ROS-mediated NLRP3 pathway in bMECs.

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Hydroxychloroquine inhibits IL-1β production from amyloid-stimulated human neutrophils

Arthritis Research & Therapy ◽

10.1186/s13075-019-2040-6 ◽

2019 ◽

Vol 21 (1) ◽

Cited By ~ 6

Author(s):

Yuya Fujita ◽

Naoki Matsuoka ◽

Jumpei Temmoku ◽

Makiko Yashiro Furuya ◽

Tomoyuki Asano ◽

...

Keyword(s):

Protein Expression ◽

Mrna Expression ◽

Nlrp3 Inflammasome ◽

Human Neutrophils ◽

Activation Process ◽

Amyloid A ◽

Caspase 1 ◽

Priming Process ◽

Significant Production

Abstract Background Hydroxychloroquine (HCQ) is used for the treatment of patients with rheumatic diseases. We tested the hypothesis that HCQ affects the NLRP3 inflammasome, which is involved in autoinflammation. Methods Human neutrophils were stimulated with serum amyloid A (SAA) in vitro and measured for IL-1β and caspase-1 (p20) secretion by ELISA. Pro-IL-1β mRNA expression in human neutrophils was quantified by real-time RT-PCR. Results SAA stimulation induced significant production of IL-1β in human neutrophils. SAA stimulation also induced NF-κB activation, pro-IL-1β mRNA expression, and NLRP3 protein expression in human neutrophils. HCQ pretreatment significantly inhibited the SAA-induced IL-1β production in human neutrophils, but did not affect the SAA-induced NF-κB activation, pro-IL-1β mRNA expression, and NLRP3 protein expression. Furthermore, SAA stimulation induced cleaved caspase-1 (p20) secretion from human neutrophils, and this release was suppressed by HCQ pretreatment. Conclusions Treatment with HCQ was associated with impaired production of IL-1β in SAA-stimulated human neutrophils without affecting the priming process of the NLRP3 inflammasome such as pro-IL-1β or NLRP3 induction. These findings suggest that HCQ affects the NLRP3 activation process, resulting in the impaired IL-1β production in human neutrophils, as representative innate immune cells.

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Abstract P291: Sodium-independent Dietary Effects on Renal Immune Cell Infiltration in Salt-sensitive Hypertension

Hypertension ◽

10.1161/hyp.70.suppl_1.p291 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Justine M Abais-Battad ◽

Hayley Lund ◽

Mingyu Liang ◽

Pengyuan Liu ◽

David L Mattson

Keyword(s):

T Cells ◽

Protein Expression ◽

Nlrp3 Inflammasome ◽

Immune Cell ◽

High Salt ◽

Coagulation Cascade ◽

Rna Expression ◽

Dietary Effects ◽

Caspase 1 ◽

Salt Sensitive Hypertension

Recent studies have shown sodium-independent dietary effects to be important in the development of Dahl SS hypertension and renal disease. Dahl SS/JrHsdMcwiCrl (SS/Crl) rats fed a grain-based diet (Teklad 5L2F) were less susceptible to salt-induced blood pressure elevation (116.5±1.2 vs 141.9±14.4 mmHg) and albuminuria (21.7±3.5 vs 162.9±22.3 mg/day) compared to SS/JrHsdMcwi (SS/Mcw) rats fed a 4.0% high salt casein-based diet (AIN-76A) for 3 weeks (n=6-8/group). Given the role of immunity in hypertension, SS/Crl rats displayed significantly less total CD45+ leukocyte infiltration in the kidney than SS/Mcw (6.1±0.9 vs 11.6±2.6 x10 6 cells/kidney). Reductions were observed in all subsequent immune cell populations, including CD3+ T cells (6.8±0.8 vs 14.4±2.2 x10 5 ), CD45R+ B cells (1.5±0.4 vs 6.7±2.2 x10 5 ), and CD11b/c+ antigen presenting cells (5.0±0.7 vs 9.2±2.1 x10 6 cells/kidney) in SS/Crl versus SS/Mcw. The SS/Crl immune system appears to be less activated, as demonstrated by a respective 44.8% and 66.8% reduction in CD4+CD25+ and CD8+CD25+ T cells, as well as a 40.4% decrease in TNFα-producing CD4+ T cells. Upon taking a discovery approach, RNA sequencing data (n=4 pools of 3 rats each) revealed genes related to hematopoietic cell lineage, the complement and coagulation cascade, B cell signaling, and primary immunodeficiency. Specifically, RNA expression of components of the NLRP3 inflammasome pathway were upregulated, including TLR4 (44.0%), NLRP3 (33.8%) and caspase-1 (26.4%), with a similar trend for IL-1β (25.4%), in the renal medulla of SS/Mcw rats fed high salt. This coincided with increased protein expression of NLRP3 (1.5-fold) and ASC (3.2-fold), together demonstrating increased NLRP3 inflammasome mRNA and protein expression in SS/Mcw rats after high salt challenge. Interestingly, RNA expression of these NLRP3 inflammasome proteins were significantly reduced in SS/Crl versus SS/Mcw rats fed high salt, including TLR4 (39.2%), NLRP3 (31.2%), caspase-1 (32.8%) and IL-1β (39.2%). These data indicate that the NLRP3 inflammasome may be a key mechanistic step in determining how these non-sodium components of the diet affect immunity, and warrant further studies to elucidate its role on salt-sensitive hypertension and renal damage.

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Is the Rigidity of SARS-CoV-2 Spike Receptor-Binding Motif the Hallmark for Its Enhanced Infectivity and Pathogenesis?

10.26434/chemrxiv.12091260.v1 ◽

2020 ◽

Cited By ~ 2

Author(s):

Angelo Spinello ◽

Andrea Saltalamacchia ◽

Alessandra Magistrato

Keyword(s):

Health Economic ◽

Global Health ◽

Receptor Binding ◽

Binding Motif ◽

Spike Glycoprotein ◽

High Affinity ◽

Global Pandemic ◽

Medical Countermeasures ◽

High Infectivity ◽

Human Receptor

<p>The latest outbreak of a new pathogenic coronavirus (SARS-CoV-2) is provoking a global health, economic and societal crisis. All-atom simulations enabled us to uncover the key molecular traits underlying the high affinity of SARS-CoV-2 spike glycoprotein towards its human receptor, providing a rationale to its high infectivity. Harnessing this knowledge can boost developing effective medical countermeasures to fight the current global pandemic.</p>

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Unique nCoV-2019 (COVID 19) spike glycoprotein processing by host protease: Analysis and Implication on infection

Current Proteomics ◽

10.2174/1570164617999200612115218 ◽

2020 ◽

Vol 17 ◽

Author(s):

Ajoy Basak ◽

Sarmistha Basak

Keyword(s):

World Health ◽

Spike Glycoprotein ◽

Binding Domains ◽

Corona Virus ◽

Global Pandemic ◽

High Infection ◽

Crucial Information ◽

Glycoprotein Processing ◽

Health Organization ◽

Host Reservoir

: The current global pandemic outbreak of a novel type of corona virus termed by World Health Organization as COVID-19 became an grave concern and worry to human health and world economy. Intense research efforts are now underway worldwide to combat and prevent the spread of this deadly disease. This zoonotic virus, a native to bat population is most likely transmitted to human via a host reservoir. Due to its close similarity to previously known SARS CoV (Severe Acute Respiratory Syndrome Corona Virus) of 2002 and related MERS CoV (Middle East Respiratory Syndrome Corona Virus) of 2012, it is also known as SARS CoV2. But unlike them it is far too infectious, virulent and lethal. Among its various proteins, the surface spike glycoprotein “S” has drawn significant attention because of its implication in viral recognition and host-virus fusion process. A detail comparative analysis of “S” proteins of SARS CoV (now called SARS CoV1), SARS CoV2 (COVID-19) and MERS CoV based on structure, sequence alignment, host cleavage sites, receptor binding domains, potential glycosylation and Cys-disulphide bridge locations has been performed. It revealed some key features and variations that may elucidate the high infection and virulence character of COVID-19. Moreover this crucial information may become useful in our quest for COVID-19 therapeutics and vaccines.

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Porphyromonas Gingivalis Infection Induces Synaptic Failure via Increased IL-1β Production in Leptomeningeal Cells

Journal of Alzheimer s Disease ◽

10.3233/jad-210031 ◽

2021 ◽

pp. 1-17

Author(s):

Wanyi Huang ◽

Fan Zeng ◽

Yebo Gu ◽

Muzhou Jiang ◽

Xinwen Zhang ◽

...

Keyword(s):

Porphyromonas Gingivalis ◽

Nlrp3 Inflammasome ◽

Cortical Neurons ◽

Inflammasome Activation ◽

Memory Decline ◽

Periodontal Bacteria ◽

Nlrp3 Inflammasome Activation ◽

Synaptic Failure ◽

Pre Treatment ◽

The Impact

Background: Studies have reported that synaptic failure occurs before the Alzheimer’s disease (AD) onset. The systemic Porphyromonas gingivalis (P. gingivalis) infection is involved in memory decline. We previously showed that leptomeningeal cells, covering the brain, activate glial cells by releasing IL-1β in response to systemic inflammation. Objective: In the present study, we focused on the impact of leptomeningeal cells on neurons during systemic P. gingivalis infection. Methods: The responses of leptomeningeal cells and cortical neurons to systemic P. gingivalis infection were examined in 15-month-old mice. The mechanism of IL-1β production by P. gingivalis infected leptomeningeal cells was examined, and primary cortical neurons were treated with P. gingivalis infected leptomeningeal cells condition medium (Pg LCM). Results: Systemic P. gingivalis infection increased the expression of IL-1β in leptomeninges and reduced the synaptophysin (SYP) expression in leptomeninges proximity cortex in mice. Leptomeningeal cells phagocytosed P. gingivalis resulting in lysosomal rupture and Cathepsin B (CatB) leakage. Leaked CatB mediated NLRP3 inflammasome activation inducing IL-1β secretion in leptomeningeal cells. Pg LCM decreased the expression of synaptic molecules, including SYP, which was inhibited by an IL-1 receptor antagonist pre-treatment. Conclusion: These observations demonstrate that P. gingivalis infection is involved in synaptic failure by inducing CatB/NLRP3 inflammasome-mediated IL-1β production in leptomeningeal cells. The periodontal bacteria-induced synaptic damage may accelerate the onset and cognitive decline of AD.

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