Modulation of Peripheral Mast Cell and Brain Microglia Axis via Kinase Inhibition.

Abstract

Background/Objectives: Kinase inhibition is a hot therapeutic strategy for several human diseases, including neurodegeneration. Tyrosine kinase c-KIT activates peripheral mast cells, while other kinases including Abelson (c-Abl) promotes autophagy and FYN mediates Tau phosphorylation. We synthesized a novel broad kinase inhibitor (BK40196) and investigated its effects on tau hyper-phosphorylation, cell loss, inflammation and behavior in transgenic rTg4510 and TgAPP (TgSwDI) mice. Methods: Drug synthesis and investigation of the pharmacokinetics and pharmacodynamics effects of BK40196 on behavior, protein levels, mast cells and microglial activity in vivo. Results: We synthesized a novel kinase inhibitor (BK40196) that exhibited high brain penetration and a potentially wide therapeutic dose. BK40196 is a dual c-KIT/c-Abl (Abelson) inhibitor but also displays binding affinity to other kinases, including fused in sarcoma (SRC) and FYN. BK40196 induces autophagy in vitro and limits the maturation of mast cells in vitro and in vivo. BK40196 significantly reduces the levels of hyper-phosphorylated tau and attenuates cell loss, while improving motor, cognitive and behavioral (anxiety) functions in models of neurodegeneration. BK40196 reduces microglial activity and the levels of brain tryptase in parallel with mast cell activation. Conclusions: BK40196 inhibits c-Kit and may play an important role in peripheral and central immunity via mast cells and microglia, respectively, and induces synergistic mechanisms through anti-inflammation and protein clearance that are mutually beneficial to alleviate neurodegenerative pathology. BK40196 is a potential candidate for the treatment of human tauopathies.