The insulin receptor inhibitor BMS-754807 alleviates neuroinflammation and Alzheimer's disease pathologies across human cellular and mouse models

Abstract

(Background) BMS-754807 is a dual inhibitor of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) that is in phase II clinical trials for the treatment of HR-positive and HER2-negative breast cancer. Because IGF-1R signaling regulates inflammatory responses, pharmacological modulation of IGF-1R may have therapeutic potential for Alzheimer’s disease (AD); however, the effects of BMS-754807 on neuroinflammatory responses/AD pathology and cognitive function have not been fully investigated. (Methods) We examined whether BMS-754807 modulates neuroinflammation and AD pathologies in multiple in vivo animal models and in vitro human models. BMS-754807 (20 mg/kg, i.p.) was systemically administered in wild-type mice challenged with LPS, 5xFAD mice, and PS19 transgenic mice. In addition, human-induced pluripotent stem cell (hiPSC)-derived microglia challenged with LPS and AD hiPSC-derived neurons were treated with 2.5 µM BMS-754807. For all models, the effects of BMS-754807 treatment were analyzed by real-time PCR, immunofluorescence staining, western blotting, ELISA, and/or activity assays. (Results) BMS-754807 treatment significantly decreased p-IGF-IR (on-target) levels, LPS-induced proinflammatory cytokine production, and reactive oxygen species levels; restored HO-1 expressions; and inhibited AKT/STAT3 signaling in BV2 microglial cells. Similarly, BMS-754807 treatment reduced LPS-evoked proinflammatory cytokine expressions in primary microglial cells and primary astrocytes. In addition, BMS-754807 administration mitigated LPS-stimulated gliosis, microglial/astrocyte-associated dynamics, STAT3/NF-κB phosphorylation, and potentially NLRP3 inflammasome in vitro and/or in WT mice. Moreover, BMS-754807 treatment suppressed LPS-mediated proinflammatory responses through IGF-1R and NLRP3 in BV2 microglial cells. In 5xFAD mice, BMS-754807