Regorafenib Regulates AD Pathology, Neuroinflammation, and Dendritic Spinogenesis in Cells and a Mouse Model of AD

Area of Science:

• Neuroscience
• Pharmacology
• Oncology

Background:

• Regorafenib is an oral multi-target kinase inhibitor used for advanced gastrointestinal stromal tumors and metastatic colorectal cancer.
• Its potential effects on neuroinflammation and Alzheimer's disease (AD) pathology remain largely uninvestigated.

Purpose of the Study:

• To investigate the regulatory function of regorafenib in neuroinflammatory responses and AD-related pathology.
• To evaluate regorafenib's effects in both in vitro and in vivo models.

Main Methods:

• Assessed regorafenib's impact on AKT signaling and lipopolysaccharide (LPS)-mediated proinflammatory cytokine expression in microglial and astrocyte cell cultures.
• Evaluated regorafenib's effects on neuroinflammation in LPS-injected wild-type mice.
• Examined regorafenib's efficacy in ameliorating AD pathology in 5x FAD mice, including dendritic spine density, Aβ plaque levels, APP processing, and tau phosphorylation.

Main Results:

• Regorafenib attenuated LPS-induced proinflammatory cytokine expression in microglial and astrocyte cells by affecting AKT signaling.
• Regorafenib suppressed LPS-induced neuroinflammatory responses in vivo.
• In 5x FAD mice, regorafenib increased dendritic spine density, decreased Aβ plaque levels, and reduced tau phosphorylation by modulating APP processing and GSK3β activity.

Conclusions:

• Regorafenib demonstrates beneficial effects on neuroinflammation and Alzheimer's disease pathology.
• The drug positively impacts dendritic spine formation and key AD pathological markers in both cellular and animal models.