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      Inflammasome activation in traumatic brain injury and Alzheimer’s disease

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          Abstract

          Traumatic brain injury (TBI) and Alzheimer’s disease (AD) represent 2 of the largest sources of death and disability in the United States. Recent studies have identified TBI as a potential risk factor for AD development, and numerous reports have shown that TBI is linked with AD associated protein expression during the acute phase of injury, suggesting an interplay between the 2 pathologies. The inflammasome is a multi-protein complex that plays a role in both TBI and AD pathologies, and is characterized by inflammatory cytokine release and pyroptotic cell death. Products of inflammasome signaling pathways activate microglia and astrocytes, which attempt to resolve pathological inflammation caused by inflammatory cytokine release and phagocytosis of cellular debris. Although the initial phase of the inflammatory response in the nervous system is beneficial, recent evidence has emerged that the heightened inflammatory response after trauma is self-perpetuating and results in additional damage in the central nervous system. Inflammasome-induced cytokines and inflammasome signaling proteins released from activated microglia interact with AD associated proteins and exacerbate AD pathological progression and cellular damage. Additionally, multiple genetic mutations associated with AD development alter microglia inflammatory activity, increasing and perpetuating inflammatory cell damage. In this review, we discuss the pathologies of TBI and AD and how they are impacted by and potentially interact through inflammasome activity and signaling proteins. We discuss current clinical trials that target the inflammasome to reduce heightened inflammation associated with these disorders.

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          A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease.

          Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices shows DAM with intracellular/phagocytic Aβ particles. Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2)(-/-) Tg-AD reveals that the DAM program is activated in a two-step process. Activation is initiated in a Trem2-independent manner that involves downregulation of microglia checkpoints, followed by activation of a Trem2-dependent program. This unique microglia-type has the potential to restrict neurodegeneration, which may have important implications for future treatment of AD and other neurodegenerative diseases. VIDEO ABSTRACT.
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            Neuroinflammation in Alzheimer's disease.

            Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease. Copyright © 2015 Elsevier Ltd. All rights reserved.
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              Inflammasomes: mechanism of assembly, regulation and signalling.

              Inflammasomes are multiprotein signalling platforms that control the inflammatory response and coordinate antimicrobial host defences. They are assembled by pattern-recognition receptors following the detection of pathogenic microorganisms and danger signals in the cytosol of host cells, and they activate inflammatory caspases to produce cytokines and to induce pyroptotic cell death. The clinical importance of inflammasomes reaches beyond infectious disease, as dysregulated inflammasome activity is associated with numerous hereditary and acquired inflammatory disorders. In this Review, we discuss the recent developments in inflammasome research with a focus on the molecular mechanisms that govern inflammasome assembly, signalling and regulation.
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                Author and article information

                Journal
                101280339
                33033
                Transl Res
                Transl Res
                Translational research : the journal of laboratory and clinical medicine
                1931-5244
                1878-1810
                12 July 2023
                April 2023
                05 September 2022
                18 July 2023
                : 254
                : 1-12
                Affiliations
                [1 ]The Miami Project to Cure Paralysis, Miami, FL, USA
                [2 ]Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL, USA
                [3 ]Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
                [4 ]Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, FL, USA
                [5 ]Center for Cognitive Neuroscience and Aging, University of Miami Miller School of Medicine, Miami, FL, USA
                Author notes
                [* ]Reprint requests: W. Dalton Dietrich, PhD, Scientific Director, The Miami Project to Cure Paralysis, Professor of Neurological Surgery, Neurology, Biomedical Engineering and Cell Biology, University of Miami, Leonard M. Miller School of Medicine, 1095 NW 14th Terrace, Suite 2-30, Miami, FL 33136-1060. ddietrich@ 123456med.miami.edu (W.D. Dietrich).
                Article
                NIHMS1913027
                10.1016/j.trsl.2022.08.014
                10353562
                36070840
                f3dd6cc1-b7a0-46c7-bb88-e35b1b163ccc

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/)

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