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GW5074 Increases Microglial Phagocytic Activities: Potential Therapeutic Direction for Alzheimer’s Disease

Microglia, the resident immune cells of the central nervous system (CNS), are responsible for maintaining homeostasis in the brain by clearing debris and are suggested to be inefficient in Alzheimer’s Disease (AD), a progressive neurodegenerative disorder for which there is no disease-modifying drug...

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Autores principales: Connor, Sarah M., Rashid, Mamunur, Ryan, Katie J., Patel, Kruti, Boyd, Justin D., Smith, Jennifer, Elyaman, Wassim, Bennett, David A., Bradshaw, Elizabeth M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9169965/
https://www.ncbi.nlm.nih.gov/pubmed/35677758
http://dx.doi.org/10.3389/fncel.2022.894601
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author Connor, Sarah M.
Rashid, Mamunur
Ryan, Katie J.
Patel, Kruti
Boyd, Justin D.
Smith, Jennifer
Elyaman, Wassim
Bennett, David A.
Bradshaw, Elizabeth M.
author_facet Connor, Sarah M.
Rashid, Mamunur
Ryan, Katie J.
Patel, Kruti
Boyd, Justin D.
Smith, Jennifer
Elyaman, Wassim
Bennett, David A.
Bradshaw, Elizabeth M.
author_sort Connor, Sarah M.
collection PubMed
description Microglia, the resident immune cells of the central nervous system (CNS), are responsible for maintaining homeostasis in the brain by clearing debris and are suggested to be inefficient in Alzheimer’s Disease (AD), a progressive neurodegenerative disorder for which there is no disease-modifying drug. Besides pathological approaches, unbiased evidence from genome-wide association studies (GWAS) and gene network analysis implicate genes expressed in microglia that reduce phagocytic ability as susceptibility genes for AD. Thus, a central feature toward AD therapy is to increase the microglial phagocytic activities while maintaining synaptic integrity. Here, we developed a robust unbiased high content screening assay to identify potential therapeutics which can reduce the amyloid-beta (Aβ1–42) load by increasing microglial uptake ability. Our screen identified the small-molecule GW5074, an inhibitor of c-RAF, a serine/threonine kinase, which significantly increased the Aβ1–42 clearance activities in human monocyte-derived microglia-like (MDMi) cells, a microglia culture model that recapitulates many genetic and phenotypic aspects of human microglia. Notably, GW5074 was previously reported to be neuroprotective for cerebellar granule cells and cortical neurons. We found that GW5074 significantly increased the expression of key AD-associated microglial molecules known to modulate phagocytosis: TYROBP, SIRPβ1, and TREM2. Our results demonstrated that GW5074 is a potential therapeutic for AD, by targeting microglia.
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spelling pubmed-91699652022-06-07 GW5074 Increases Microglial Phagocytic Activities: Potential Therapeutic Direction for Alzheimer’s Disease Connor, Sarah M. Rashid, Mamunur Ryan, Katie J. Patel, Kruti Boyd, Justin D. Smith, Jennifer Elyaman, Wassim Bennett, David A. Bradshaw, Elizabeth M. Front Cell Neurosci Neuroscience Microglia, the resident immune cells of the central nervous system (CNS), are responsible for maintaining homeostasis in the brain by clearing debris and are suggested to be inefficient in Alzheimer’s Disease (AD), a progressive neurodegenerative disorder for which there is no disease-modifying drug. Besides pathological approaches, unbiased evidence from genome-wide association studies (GWAS) and gene network analysis implicate genes expressed in microglia that reduce phagocytic ability as susceptibility genes for AD. Thus, a central feature toward AD therapy is to increase the microglial phagocytic activities while maintaining synaptic integrity. Here, we developed a robust unbiased high content screening assay to identify potential therapeutics which can reduce the amyloid-beta (Aβ1–42) load by increasing microglial uptake ability. Our screen identified the small-molecule GW5074, an inhibitor of c-RAF, a serine/threonine kinase, which significantly increased the Aβ1–42 clearance activities in human monocyte-derived microglia-like (MDMi) cells, a microglia culture model that recapitulates many genetic and phenotypic aspects of human microglia. Notably, GW5074 was previously reported to be neuroprotective for cerebellar granule cells and cortical neurons. We found that GW5074 significantly increased the expression of key AD-associated microglial molecules known to modulate phagocytosis: TYROBP, SIRPβ1, and TREM2. Our results demonstrated that GW5074 is a potential therapeutic for AD, by targeting microglia. Frontiers Media S.A. 2022-05-23 /pmc/articles/PMC9169965/ /pubmed/35677758 http://dx.doi.org/10.3389/fncel.2022.894601 Text en Copyright © 2022 Connor, Rashid, Ryan, Patel, Boyd, Smith, Elyaman, Bennett and Bradshaw. https://creativecommons.org/licenses/by/4.0/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.
spellingShingle Neuroscience
Connor, Sarah M.
Rashid, Mamunur
Ryan, Katie J.
Patel, Kruti
Boyd, Justin D.
Smith, Jennifer
Elyaman, Wassim
Bennett, David A.
Bradshaw, Elizabeth M.
GW5074 Increases Microglial Phagocytic Activities: Potential Therapeutic Direction for Alzheimer’s Disease
title GW5074 Increases Microglial Phagocytic Activities: Potential Therapeutic Direction for Alzheimer’s Disease
title_full GW5074 Increases Microglial Phagocytic Activities: Potential Therapeutic Direction for Alzheimer’s Disease
title_fullStr GW5074 Increases Microglial Phagocytic Activities: Potential Therapeutic Direction for Alzheimer’s Disease
title_full_unstemmed GW5074 Increases Microglial Phagocytic Activities: Potential Therapeutic Direction for Alzheimer’s Disease
title_short GW5074 Increases Microglial Phagocytic Activities: Potential Therapeutic Direction for Alzheimer’s Disease
title_sort gw5074 increases microglial phagocytic activities: potential therapeutic direction for alzheimer’s disease
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9169965/
https://www.ncbi.nlm.nih.gov/pubmed/35677758
http://dx.doi.org/10.3389/fncel.2022.894601
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