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      DAPT Attenuates Cadmium-Induced Toxicity in Mice by Inhibiting Inflammation and the Notch/HES-1 Signaling Axis

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          Abstract

          The small molecule DAPT inhibits the Notch signaling pathway by blocking γ-secretase mediated Notch cleavage. Given the critical role of the Notch signaling axis in inflammation, we asked whether DAPT could block Notch-mediated inflammation and thus exert neuronal protection. We established a mouse model of chronic exposure to cadmium (Cd)-induced toxicity and treated it with DAPT. DAPT was effective in ameliorating Cd-induced multi-organ damage and cognitive impairment in mice, as DAPT restored abnormal performance in the Y-maze, forced swimming and Morris water maze (MWM) tests. DAPT also reversed Cd-induced neuronal loss and glial cell activation to normal as observed by immunofluorescence and immunohistochemistry of brain tissue sections. In addition, Cd-intoxicated mice showed significantly increased levels of the Notch/HES-1 signaling axis and NF-κB, as well as decreased levels of the inflammatory inhibitors C/EBPβ and COP1. However, DAPT down regulated the elevated Notch/HES-1 signaling axis to normal, eliminating inflammation and thus protecting the nervous system. Thus, DAPT effectively eliminated the neurotoxicity of Cd, and blocking γ-secretase as well as Notch signaling axis may be a potential target for the development of neuronal protective drugs.

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          Most cited references26

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          The canonical Notch signaling pathway: unfolding the activation mechanism.

          Notch signaling regulates many aspects of metazoan development and tissue renewal. Accordingly, the misregulation or loss of Notch signaling underlies a wide range of human disorders, from developmental syndromes to adult-onset diseases and cancer. Notch signaling is remarkably robust in most tissues even though each Notch molecule is irreversibly activated by proteolysis and signals only once without amplification by secondary messenger cascades. In this Review, we highlight recent studies in Notch signaling that reveal new molecular details about the regulation of ligand-mediated receptor activation, receptor proteolysis, and target selection.
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            TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia.

            Genetic variants of TREM2, a protein expressed selectively by microglia in the brain, are associated with Alzheimer's disease (AD). Starting from an unbiased protein microarray screen, we identified a set of lipoprotein particles (including LDL) and apolipoproteins (including CLU/APOJ and APOE) as ligands of TREM2. Binding of these ligands by TREM2 was abolished or reduced by disease-associated mutations. Overexpression of wild-type TREM2 was sufficient to enhance uptake of LDL, CLU, and APOE in heterologous cells, whereas TREM2 disease variants were impaired in this activity. Trem2 knockout microglia showed reduced internalization of LDL and CLU. β-amyloid (Aβ) binds to lipoproteins and this complex is efficiently taken up by microglia in a TREM2-dependent fashion. Uptake of Aβ-lipoprotein complexes was reduced in macrophages from human subjects carrying a TREM2 AD variant. These data link three genetic risk factors for AD and reveal a possible mechanism by which mutant TREM2 increases risk of AD. VIDEO ABSTRACT.
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              The Y-Maze for Assessment of Spatial Working and Reference Memory in Mice.

              The Y-maze can be used to assess short term memory in mice. Spontaneous alternation, a measure of spatial working memory, can be assessed by allowing mice to explore all three arms of the maze and is driven by an innate curiosity of rodents to explore previously unvisited areas. A mouse with intact working memory, and hence intact prefrontal cortical functions, will remember the arms previously visited and show a tendency to enter a less recently visited arm. Spatial reference memory, which is underlined by the hippocampus, can also be tested by placing the test mice into the Y-maze with one arm closed off during training. After an inter-trial interval of for example 1 h, the mouse should remember which arm it has not explored previously and should visit this arm more often. This chapter describes the pre-test conditions, the materials required and the protocol for conducting and interpreting the results of these two related tests.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                29 April 2022
                2022
                : 13
                : 902796
                Affiliations
                [1] 1 Key Laboratory of Ecology and Environment in Minority Areas National Ethnic Affairs Commission , Center for Translational Neuroscience , College of Life and Environmental Sciences , Minzu University of China , Beijing, China
                [2] 2 Department of Cell Biology and Medical Genetics , School of Basic Medical Sciences , Shenzhen University Health Science Center , Shenzhen, China
                Author notes

                Edited by: Rui Liu, Chinese Academy of Medical Sciences, China

                Reviewed by: Long-Chuan Yu, Peking University, China

                Jianjun Zhang, Institute of Psychology (CAS), China

                *Correspondence: Yang Hu, yang.hu@ 123456muc.edu.cn ; Rongfeng Lan, lan@ 123456szu.edu.cn ,

                This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology

                Article
                902796
                10.3389/fphar.2022.902796
                9100577
                35571137
                4ed1822c-def2-4107-8538-f99f63fad66b
                Copyright © 2022 Yang, Shen, Wang, Dai, Qin, Hu and Lan.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 23 March 2022
                : 15 April 2022
                Funding
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 81773088 21888038
                Categories
                Pharmacology
                Original Research

                Pharmacology & Pharmaceutical medicine
                gfap,γ-secretase,hes-1,iba1,map2
                Pharmacology & Pharmaceutical medicine
                gfap, γ-secretase, hes-1, iba1, map2

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