Anti‐inflammatory clearance of amyloid beta by a chimeric Gas6 fusion protein

Abstract Background Aβ immunotherapy is the most promising approach in treating Alzheimer’s disease (AD). Although Aβ‐antibodies can substantially reduce Aβ burden in the brain, solutions for antibody‐induced inflammation and subsequent ARIA (Amyloid‐related imaging abnormalities) are still in demand. Here we developed a novel chimeric protein platform, GAIA (Gas6‐mediated anti‐inflammatory adaptor). GAIA platform utilizes TAM receptors, which are expressed on glial cells and mediate phagocytosis without associated inflammatory response. Method We developed a GAIA‐based novel chimeric protein (αAβ‐Gas6) which is composed of two distinct functional domains; a single‐chain variable fragment of Aducanumab, which selectively binds to Aβ, fused with Gas6, a TAM receptor‐binding domain. Aβ clearance and phagocytosis‐associated inflammatory responses of αAβ‐Gas6 were measured in comparison with Aducanumab. Result αAβ‐Gas6 showed selective uptake of Aβ through phagocytosis in vitro. While Aducanumab induced phagocytosis only in primary microglia, αAβ‐Gas6 significantly induced phagocytosis in both cultured microglia and astrocyte. In comparison with Aducanumab, αAβ‐Gas6 secreted significantly lower amount of pro‐inflammatory cytokines, such as TNF, IL‐6, and IL‐1β. In vivo application of αAβ‐Gas6 reduced Aβ burden in an extent significantly lower in mice treated with Aducanumab. Finally, αAβ‐Gas6 groups showed significantly reduced excessive synapse elimination levels comparable to non‐AD wild type groups. Conclusion We developed a novel chimeric fusion protein αAβ‐Gas6 by engineering TAM receptor‐binding domain Gas6. In comparison with antibody drug, αAβ‐Gas6 showed advanced amyloid clearance, significantly reduced neuroinflammation, and neurotoxicity. Thus, our results suggest a novel immunotherapeutic agent which can bifunctionally target Aβ and modulate gilal cells to reduce neuroinflammation.