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

• Published in: Frontiers in cellular neuroscience Vol. 16; p. 894601
• Main Authors: Connor, Sarah M., Rashid, Mamunur, Ryan, Katie J., Patel, Kruti, Boyd, Justin D., Smith, Jennifer, Elyaman, Wassim, Bennett, David A., Bradshaw, Elizabeth M.
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 23.05.2022; Frontiers Media S.A
• Subjects: Alzheimer's disease; Apoptosis; c-RAF; Cell culture; Central nervous system; Cerebellum; Consent; Dementia; Genome-wide association studies; Genomes; Granule cells; GW5074; high content drug screening; Homeostasis; Human subjects; Immune clearance; Kinases; Memory; Microglia; Monocytes; Neurodegeneration; Neurodegenerative diseases; Neuroprotection; Neuroscience; Phagocytes; Phagocytosis; Protein-serine/threonine kinase; TREM2; Minneapolis Minnesota; New York; United States > US; GW5074; TYROBP; Alzheimer’s disease; c-RAF; high content drug screening; TREM2; microglia
• ISSN: 1662-5102; 1662-5102
• DOI: 10.3389/fncel.2022.894601

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.