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      In Vivo TSPO Signal and Neuroinflammation in Alzheimer’s Disease

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          Abstract

          In the last decade, positron emission tomography (PET) and single-photon emission computed tomography (SPECT) in in vivo imaging has attempted to demonstrate the presence of neuroinflammatory reactions by measuring the 18 kDa translocator protein (TSPO) expression in many diseases of the central nervous system. We focus on two pathological conditions for which neuropathological studies have shown the presence of neuroinflammation, which translates in opposite in vivo expression of TSPO. Alzheimer’s disease has been the most widely assessed with more than forty preclinical and clinical studies, showing overall that TSPO is upregulated in this condition, despite differences in the topography of this increase, its time-course and the associated cell types. In the case of schizophrenia, a reduction of TSPO has instead been observed, though the evidence remains scarce and contradictory. This review focuses on the key characteristics of TSPO as a biomarker of neuroinflammation in vivo, namely, on the cellular origin of the variations in its expression, on its possible biological/pathological role and on its variations across disease phases.

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          Neurotoxic reactive astrocytes are induced by activated microglia

          A reactive astrocyte subtype termed A1 is induced after injury or disease of the central nervous system and subsequently promotes the death of neurons and oligodendrocytes.
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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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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                21 August 2020
                September 2020
                : 9
                : 9
                Affiliations
                [1 ]Division of Adult Psychiatry, Department of Psychiatry, University Hospitals of Geneva, 1205 Geneva, Switzerland; stergios.tsartsalis@ 123456hcuge.ch (S.T.); kelly.ceyzeriat@ 123456unige.ch (K.C.); philippe.millet@ 123456hcuge.ch (P.M.)
                [2 ]Department of Psychiatry, University of Geneva, 1211 Geneva, Switzerland
                [3 ]Division of Nuclear Medicine and Molecular Imaging, Diagnostic Department, Geneva University and Geneva University Hospitals, 1205 Geneva, Switzerland; valentina.garibotto@ 123456hcuge.ch
                [4 ]Division of Radiation Oncology, Department of Oncology, University Hospitals of Geneva, 1205 Geneva, Switzerland
                Author notes
                [* ]Correspondence: benjamin.tournier@ 123456hcuge.ch ; Tel.: +41-22-305-5379
                Article
                cells-09-01941
                10.3390/cells9091941
                7565089
                32839410
                7978d93b-96ff-40d5-82b5-0a0b6233a31b
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                Categories
                Review

                tspo,alzheimer’s disease,schizophrenia,astrocytes,microglia

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