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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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2022.894601/full |
| _version_ | 1818530552760762368 |
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| author | Sarah M. Connor Mamunur Rashid Katie J. Ryan Kruti Patel Justin D. Boyd Jennifer Smith Wassim Elyaman Wassim Elyaman David A. Bennett Elizabeth M. Bradshaw Elizabeth M. Bradshaw |
| author_facet | Sarah M. Connor Mamunur Rashid Katie J. Ryan Kruti Patel Justin D. Boyd Jennifer Smith Wassim Elyaman Wassim Elyaman David A. Bennett Elizabeth M. Bradshaw Elizabeth M. Bradshaw |
| author_sort | Sarah M. Connor |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-11T17:21:09Z |
| format | Article |
| id | doaj.art-aae45228f8e44a1e986ed26144c32b60 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-11T17:21:09Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-aae45228f8e44a1e986ed26144c32b602022-12-22T00:57:09ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022022-05-011610.3389/fncel.2022.894601894601GW5074 Increases Microglial Phagocytic Activities: Potential Therapeutic Direction for Alzheimer’s DiseaseSarah M. Connor0Mamunur Rashid1Katie J. Ryan2Kruti Patel3Justin D. Boyd4Jennifer Smith5Wassim Elyaman6Wassim Elyaman7David A. Bennett8Elizabeth M. Bradshaw9Elizabeth M. Bradshaw10Columbia University Irving Medical Center, New York, NY, United StatesColumbia University Irving Medical Center, New York, NY, United StatesAnn Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, United StatesAnn Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, United StatesLaboratory for Drug Discovery in Neurodegeneration at the Harvard NeuroDiscovery Center, Harvard Medical School, Boston, MA, United StatesThe Institute of Chemistry and Cell Biology (ICCB)-Longwood Screening Facility, Harvard Medical School, Boston, MA, United StatesColumbia University Irving Medical Center, New York, NY, United StatesTaub Institute for Research on Alzheimer’s Disease and the Aging Brain, New York, NY, United StatesAlzheimer Disease Center, Rush University Medical Center, Chicago, IL, United StatesColumbia University Irving Medical Center, New York, NY, United StatesTaub Institute for Research on Alzheimer’s Disease and the Aging Brain, New York, NY, United StatesMicroglia, 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.https://www.frontiersin.org/articles/10.3389/fncel.2022.894601/fullAlzheimer’s diseasemicrogliaGW5074c-RAFhigh content drug screeningTREM2 |
| spellingShingle | Sarah M. Connor Mamunur Rashid Katie J. Ryan Kruti Patel Justin D. Boyd Jennifer Smith Wassim Elyaman Wassim Elyaman David A. Bennett Elizabeth M. Bradshaw Elizabeth M. Bradshaw GW5074 Increases Microglial Phagocytic Activities: Potential Therapeutic Direction for Alzheimer’s Disease Frontiers in Cellular Neuroscience Alzheimer’s disease microglia GW5074 c-RAF high content drug screening TREM2 |
| 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 | Alzheimer’s disease microglia GW5074 c-RAF high content drug screening TREM2 |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2022.894601/full |
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