Multi target kinase inhibitor X regulates AD pathology, neuroinflammation, as well as dendritic spinogenesis

Abstract

The oral mulit-target kinase inhibitor X is inhibits oncogenic receptor tyrosine kinase (RTK) and is an effective targeted therapy for patients with metastatic colorectal cancer as well as advanced gastrointestinal stromal tumors. However, whether X can affects neuroinflammation and AD pathology is not well studied. Thus, we tested the effects of X on neuroinflammatory responses and found that X regulates LPS-induced neuroinflammatory responses in glial cells, wild-type mice, and 5x FAD mice (a mouse model of AD). X affects TLR4/AKT/STAT3 signaling to alter LPS-mediated proinflammatory cytokine levels, suggesting that X can suppress LPS-mediated neuroinflammation in vitro and in vivo. We then examined whether X can alter AD pathology and found that X -injected 5x FAD mice increased dendritic spine density, decreased A plaque levels by modulating APP processing and autophagy ATG12 levels. Importantly, X -injected 5x FAD mice significantly reduced tau phosphorylation at AT100 by downregulating tau kinase p-GSK3. Taken together, our results indicate that X can regulates AD pathology, neuroinflammation, and dendritic spine formation.