AXL activation leads to reduced amyloid plaque deposition in APP/PS‐1 mice

Abstract

AbstractBackgroundMicroglia, the immune cells of the brain, play seemingly antagonistic roles in the Alzheimer’s disease (AD) brain. On one hand, microglia contribute to clearance of amyloid beta (Aβ) plaques via phagocytosis. On the other hand, activated microglia produce inflammatory cytokines that contribute to a hostile neuronal environment, exacerbating AD pathogenesis. Axl, a member of the TAM receptor family, is increased on microglia that surround Aβ plaques. Gas6, the primary ligand for Axl, promotes phagocytosis and suppresses inflammation in peripheral immune cells.MethodTo test the hypothesis that manipulation of the Axl‐Gas6 pathway contributes to Aβ clearance, we carried out intrahippocampal injections of an AAV‐Gas6 vector in male and female APP/PS‐1 mice at 4 or 7 months of age.ResultHippocampal overexpression of Gas6 for one or six months led to decreased Aβ plaque load when compared to the opposite hippocampus injected with a control AAV‐Gas6(delta) vector that lacks the Gla and EGF domains required for Axl phosphorylation. We are currently quantifying microglial responses in these brains as well as carrying out in vitro studies with microglia from Axl knockout mice to better determine the roles of the Gas6‐Axl signaling pathway in mediating Aβ phagocytosis and microglial inflammatory responses.ConclusionAxl activation in vivo leads to reduced Aβ plaque load. Results from this work will provide insight regarding potential mechanisms that may be harnessed to reduce AD‐related pathology.