Presenter of 1 Presentation
ANTI-INFLAMMATORY CLEARANCE OF AMYLOID BETA BY A CHIMERIC GAS6 FUSION PROTEIN
Abstract
Aims
Clearing amyloid-beta (Aβ) through immunotherapy is one of the most promising therapeutic approaches to Alzheimer’s disease (AD). Although several monoclonal antibodies against Aβ have been shown to substantially reduce Aβ burden in AD patients, their effects on improving cognitive function remain marginal. In addition, a significant portion of patients treated with Aβ-targeting antibodies experience brain edema and microhemorrhage associated with antibody-mediated Fc receptor activation in the brain. Therefore, the challenge of future AD treatments is to develop a therapeutic that robustly eliminates Aβ without inducing the pro-inflammatory side effects commonly associated with conventional antibodies.
Methods
In order to solve the dilemma of conventional antibody drugs, we develop a novel phagocytosis inducer for Aβ consisting of a single chain variable fragment (scFv) of an Aβ-targeting monoclonal antibody fused with a truncated receptor binding domain of Gas6, a bridging molecule for the clearance of dead cells via TAM (Tyro3, Axl, and MerTK) receptors.
Results
This chimeric fusion protein (αAβ-Gas6) selectively eliminates Aβ plaques mainly through Axl receptor-dependent phagocytosis without inducing NF-kB-mediated inflammatory responses or reactive gliosis. Furthermore, αAβ-Gas6 can induce synergistic clearance of Aβ by activating both microglial and astrocytic phagocytosis, resulting in better behavioral outcomes with substantially reduced synapse elimination in AD model mice compared to Aβ antibody treatment.
Conclusions
Our results suggest that αAβ-Gas6 can be a novel immunotherapeutic agent for AD that overcomes the side effects of conventional antibody therapy.