c-KIT inhibitors reduce pathology and improve behavior in the Tg(SwDI) model of Alzheimer’s disease

• DOI: 10.26508/lsa.202402625
• Publication Date: 2024-07-15T15:00:18Z
• Authors: Max Stevenson; Michaeline L Hebron; Xiaoguang Liu; Kaluvu Balaraman; Christian Wolf; Charbel Moussa
• Keywords: Cognitive Decline

Treatments for Alzheimer's disease have primarily focused on removing brain amyloid plaques to improve cognitive outcomes in patients. We developed small compounds, known as BK40143 and BK40197, we hypothesize that these drugs alleviate microglial-mediated neuroinflammation induce autophagic clearance of neurotoxic proteins behavior models neurodegeneration. Specificity binding assays BK40197 showed primary c-KIT/Platelet Derived Growth Factor Receptors (PDGFR)α/β, whereas also differentially binds FYVE finger-containing phosphoinositide kinase (PIKFYVE). Both compounds penetrate the CNS, treatment with inhibited maturation peripheral mast cells transgenic mice, correlating improvements measures memory anxiety. In brain, microglial activation was profoundly attenuated amyloid-beta tau were reduced via autophagy. Multi-kinase inhibition, including c-KIT, exerts multifunctional effects reduce neurodegenerative pathology autophagy activity may represent a potential therapeutic option