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

Frontiers in Cellular Neuroscience

David A. Bennett¹  Katie J. Ryan²  Kruti Patel²  Sarah M. Connor³  Mamunur Rashid³  Justin D. Boyd⁴  Elizabeth M. Bradshaw⁵  Wassim Elyaman⁵  Jennifer Smith⁶ 

[1] Alzheimer Disease Center, Rush University Medical Center, Chicago, IL, United States;Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, United States;Columbia University Irving Medical Center, New York, NY, United States;Laboratory for Drug Discovery in Neurodegeneration at the Harvard NeuroDiscovery Center, Harvard Medical School, Boston, MA, United States;Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, New York, NY, United States;The Institute of Chemistry and Cell Biology (ICCB)-Longwood Screening Facility, Harvard Medical School, Boston, MA, United States;

关键词: Alzheimer’s disease;    microglia;    GW5074;    c-RAF;    high content drug screening;    TREM2;   

DOI  :  10.3389/fncel.2022.894601

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown