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      Oral administration of Pantoea agglomerans-derived lipopolysaccharide prevents metabolic dysfunction and Alzheimer’s disease-related memory loss in senescence-accelerated prone 8 (SAMP8) mice fed a high-fat diet

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          Abstract

          The pathogenesis of Alzheimer’s disease (AD) remains unclear, but an imbalance between the production and clearance of amyloid-β (Aβ) peptides is known to play a critical role in AD progression. A promising preventative approach is to enhance the normal Aβ clearance activity of brain phagocytes such as microglia. In mice, the intraperitoneal injection of Toll-like receptor 4 agonist was shown to enhance Aβ clearance and exhibit a preventative effect on AD-related pathology. Our previous clinical study demonstrated that orally administered Pantoea agglomerans-derived lipopolysaccharide (LPSp) exhibited an LDL (low-density lipoprotein)-lowering effect in human volunteers with hyperlipidemia, a known risk factor for AD. In vitro studies have shown that LPSp treatment increases Aβ phagocytosis by microglial cells; however it is still unclear whether orally administered LPSp exhibits a preventive effect on AD progression. We show here that in senescence-accelerated prone 8 (SAMP8) mice fed a high-fat diet, oral administration of LPSp at 0.3 or 1 mg/kg body weight·day for 18 weeks significantly improved glucose metabolism and lipid profiles. The LPSp treatment also reduced pro-inflammatory cytokine expression and oxidative-burst activity in the peripheral blood. Moreover, LPSp significantly reduced brain Aβ burden and memory impairment as seen in the water maze test, although we could not confirm a significant enhancement of Aβ phagocytosis in microglia isolated from the brains after treatment. Taken together, our results show that LPSp holds promise as a preventative therapy for AD or AD-related diseases induced by impairment of metabolic functions.

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          Most cited references45

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          Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits.

          Infection with antibiotic-resistant bacteria, such as vancomycin-resistant Enterococcus (VRE), is a dangerous and costly complication of broad-spectrum antibiotic therapy. How antibiotic-mediated elimination of commensal bacteria promotes infection by antibiotic-resistant bacteria is a fertile area for speculation with few defined mechanisms. Here we demonstrate that antibiotic treatment of mice notably downregulates intestinal expression of RegIIIgamma (also known as Reg3g), a secreted C-type lectin that kills Gram-positive bacteria, including VRE. Downregulation of RegIIIgamma markedly decreases in vivo killing of VRE in the intestine of antibiotic-treated mice. Stimulation of intestinal Toll-like receptor 4 by oral administration of lipopolysaccharide re-induces RegIIIgamma, thereby boosting innate immune resistance of antibiotic-treated mice against VRE. Compromised mucosal innate immune defence, as induced by broad-spectrum antibiotic therapy, can be corrected by selectively stimulating mucosal epithelial Toll-like receptors, providing a potential therapeutic approach to reduce colonization and infection by antibiotic-resistant microbes.
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            Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS.

            Amyotrophic lateral sclerosis (ALS) is a progressive disease associated with neuronal cell death that is thought to involve aberrant immune responses. Here we investigated the role of innate immunity in a mouse model of ALS. We found that inflammatory monocytes were activated and that their progressive recruitment to the spinal cord, but not brain, correlated with neuronal loss. We also found a decrease in resident microglia in the spinal cord with disease progression. Prior to disease onset, splenic Ly6Chi monocytes expressed a polarized macrophage phenotype (M1 signature), which included increased levels of chemokine receptor CCR2. As disease onset neared, microglia expressed increased CCL2 and other chemotaxis-associated molecules, which led to the recruitment of monocytes to the CNS by spinal cord-derived microglia. Treatment with anti-Ly6C mAb modulated the Ly6Chi monocyte cytokine profile, reduced monocyte recruitment to the spinal cord, diminished neuronal loss, and extended survival. In humans with ALS, the analogous monocytes (CD14+CD16-) exhibited an ALS-specific microRNA inflammatory signature similar to that observed in the ALS mouse model, linking the animal model and the human disease. Thus, the profile of monocytes in ALS patients may serve as a biomarker for disease stage or progression. Our results suggest that recruitment of inflammatory monocytes plays an important role in disease progression and that modulation of these cells is a potential therapeutic approach.
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              CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation.

              Microglia are the brain's tissue macrophages and are found in an activated state surrounding beta-amyloid plaques in the Alzheimer's disease brain. Microglia interact with fibrillar beta-amyloid (fAbeta) through an ensemble of surface receptors composed of the alpha(6)beta(1) integrin, CD36, CD47, and the class A scavenger receptor. These receptors act in concert to initiate intracellular signaling cascades and phenotypic activation of these cells. However, it is unclear how engagement of this receptor complex is linked to the induction of an activated microglial phenotype. We report that the response of microglial cells to fibrillar forms of Abeta requires the participation of Toll-like receptors (TLRs) and the coreceptor CD14. The response of microglia to fAbeta is reliant upon CD14, which act together with TLR4 and TLR2 to bind fAbeta and to activate intracellular signaling. We find that cells lacking these receptors could not initiate a Src-Vav-Rac signaling cascade leading to reactive oxygen species production and phagocytosis. The fAbeta-mediated activation of p38 MAPK also required CD14, TLR4, and TLR2. Inhibition of p38 abrogated fAbeta-induced reactive oxygen species production and attenuated the induction of phagocytosis. Microglia lacking CD14, TLR4, and TLR2 showed no induction of phosphorylated IkappaBalpha following fAbeta. These data indicate these innate immune receptors function as members of the microglial fAbeta receptor complex and identify the signaling mechanisms whereby they contribute to microglial activation.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: Project administrationRole: Resources
                Role: Resources
                Role: Resources
                Role: Resources
                Role: Resources
                Role: ConceptualizationRole: Funding acquisitionRole: ResourcesRole: Supervision
                Role: ConceptualizationRole: Funding acquisitionRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                1 June 2018
                2018
                : 13
                : 6
                : e0198493
                Affiliations
                [1 ] Departments of Integrated and Holistic Immunology, Faculty of Medicine, Kagawa University, Kagawa, Japan
                [2 ] Control of Innate Immunity, Technology Research Association, Kagawa, Japan
                [3 ] Research Institute for Healthy Living, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan
                [4 ] Macrophi Inc., Kagawa, Japan
                [5 ] Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka, Japan
                [6 ] Department of Applied Biological Science, Faculty of Agriculture, Kagawa University, Kagawa, Japan
                The University of Tokyo, JAPAN
                Author notes

                Competing Interests: CK is employed by Macrophi Inc. KK, HT and TM are employed by Hamamatsu Photonics K.K. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0003-0253-077X
                Article
                PONE-D-18-08810
                10.1371/journal.pone.0198493
                5983504
                29856882
                bac1f064-b54d-43dd-b4f1-0d983300bd03
                © 2018 Kobayashi et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 28 March 2018
                : 20 May 2018
                Page count
                Figures: 8, Tables: 1, Pages: 23
                Funding
                This work was supported by the Council for Science, Technology and Innovation (CSTI), Cross-ministerial Strategic Innovation Promotion Program (SIP) and‘Technologies for creating next-generation agriculture, forestry and fisheries’ (funding agency: Bio-oriented Technology Research Advancement Institution, NARO). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CK is employed by Macrophi Inc. The funder provided support in the form of salaries for author [CK], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. KK, HT and TM are employed by Hamamatsu Photonics K.K. The funder provided support in the form of salaries for authors [KK, HT and TM],but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.
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