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      Selective disruption of TLR2-MyD88 interaction inhibits inflammation and attenuates Alzheimer’s pathology

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          Abstract

          Induction of TLR2 activation depends on its association with the adapter protein MyD88. We have found that TLR2 and MyD88 levels are elevated in the hippocampus and cortex of patients with Alzheimer’s disease (AD) and in a 5XFAD mouse model of AD. Since there is no specific inhibitor of TLR2, to target induced TLR2 from a therapeutic angle, we engineered a peptide corresponding to the TLR2-interacting domain of MyD88 (TIDM) that binds to the BB loop of only TLR2, and not other TLRs. Interestingly, WT TIDM peptide inhibited microglial activation induced by fibrillar Aβ1-42 and lipoteichoic acid, but not 1-methyl-4-phenylpyridinium, dsRNA, bacterial lipopolysaccharide, flagellin, or CpG DNA. After intranasal administration, WT TIDM peptide reached the hippocampus, reduced hippocampal glial activation, lowered Aβ burden, attenuated neuronal apoptosis, and improved memory and learning in 5XFAD mice. However, WT TIDM peptide was not effective in 5XFAD mice lacking TLR2. In addition to its effects in 5XFAD mice, WT TIDM peptide also suppressed the disease process in mice with experimental allergic encephalomyelitis and collagen-induced arthritis. Therefore, selective targeting of the activated status of 1 component of the innate immune system by WT TIDM peptide may be beneficial in AD as well as other disorders in which TLR2/MyD88 signaling plays a role in disease pathogenesis.

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          Assembly and localization of Toll-like receptor signalling complexes.

          Signal transduction by the Toll-like receptors (TLRs) is central to host defence against many pathogenic microorganisms and also underlies a large burden of human disease. Thus, the mechanisms and regulation of signalling by TLRs are of considerable interest. In this Review, we discuss the molecular basis for the recognition of pathogen-associated molecular patterns, the nature of the protein complexes that mediate signalling, and the way in which signals are regulated and integrated at the level of allosteric assembly, post-translational modification and subcellular trafficking of the components of the signalling complexes. These fundamental molecular mechanisms determine whether the signalling output leads to a protective immune response or to serious pathologies such as sepsis. A detailed understanding of these processes at the molecular level provides a rational framework for the development of new drugs that can specifically target pathological rather than protective signalling in inflammatory and autoimmune disease.
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            Inferences, questions and possibilities in Toll-like receptor signalling.

            The Toll-like receptors (TLRs) are the key proteins that allow mammals--whether immunologically naive or experienced--to detect microbes. They lie at the core of our inherited resistance to disease, initiating most of the phenomena that occur in the course of infection. Quasi-infectious stimuli that have been used for decades to study inflammatory mechanisms can activate the TLR family of proteins. And it now seems that many inflammatory processes, both sterile and infectious, may depend on TLR signalling. We are in a good position to apply our understanding of TLR signalling to a range of challenges in immunology and medicine.
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              Overview and findings from the religious orders study.

              The Religious Orders Study is a longitudinal clinical-pathologic cohort study of aging and Alzheimer's disease (AD). In this manuscript, we summarize the study methods including the study design and describe the clinical evaluation, assessment of risk factors, collection of ante-mortem biological specimens, brain autopsy and collection of selected postmortem data. (1) review the relation of neuropathologic indices to clinical diagnoses and cognition proximate to death; (2) examine the relation of risk factors to clinical outcomes; (3) examine the relation of risk factors to measures of neuropathology; and (4) summarize additional study findings. We then discuss and contextualize the study findings.
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                Author and article information

                Contributors
                Journal
                J Clin Invest
                J. Clin. Invest
                J Clin Invest
                The Journal of Clinical Investigation
                American Society for Clinical Investigation
                0021-9738
                1558-8238
                10 July 2018
                4 September 2018
                1 October 2018
                1 October 2018
                : 128
                : 10
                : 4297-4312
                Affiliations
                [1 ]Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
                [2 ]Barrow Neurological Institute, Phoenix, Arizona, USA.
                [3 ]Medicinal and Synthetic Chemistry Core, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois, USA.
                [4 ]High Throughput Analysis Laboratory and Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA.
                [5 ]Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
                [6 ]Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.
                Author notes
                Address correspondence to: Kalipada Pahan, Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, Suite 310, Chicago, Illinois 60612, USA. Phone: 312.563.3592; Email: Kalipada_Pahan@ 123456rush.edu .

                Authorship note: SBR, MJ, AR, and GTC contributed equally to this work.

                Author information
                http://orcid.org/0000-0003-3606-9686
                http://orcid.org/0000-0001-6048-9598
                Article
                96209
                10.1172/JCI96209
                6159992
                29990310
                39e5c0a9-6a74-4042-a11a-591eeae5935c
                Copyright © 2018 Rangasamy et al.

                This work is licensed under the Creative Commons Attribution 4.0 International License.

                History
                : 11 July 2017
                : 3 July 2018
                Funding
                Funded by: NIH Office of the Director, https://doi.org/10.13039/100000052;
                Award ID: AG050431
                Funded by: U.S. Army Medical Research and Materiel Command
                Award ID: W81XWH-12-1-0065
                Funded by: Zenith Fellows Award from Alzheimer’s Association
                Award ID: ZEN-17-438829
                Funded by: US Department of Veterans Affairs
                Award ID: 1I01BX003033
                Categories
                Research Article

                inflammation,neuroscience,alzheimer’s disease,autoimmune diseases,innate immunity

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