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

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An engineered protein engages the efferocytosis pathway to induce amyloid-beta engulfment, resulting in behavioral rescue in Alzheimer's disease mouse models without the increased inflammation or vascular pathology associated with conventional antibody therapy Clearing amyloid-beta (A beta) through immunotherapy is one of the most promising therapeutic approaches to Alzheimer's disease (AD). Although several monoclonal antibodies against A beta have been shown to substantially reduce A beta burden in patients with AD, their effects on improving cognitive function remain marginal. In addition, a significant portion of patients treated with A beta-targeting antibodies experience brain edema and microhemorrhage associated with antibody-mediated Fc receptor activation in the brain. Here, we develop a phagocytosis inducer for A beta consisting of a single-chain variable fragment of an A beta-targeting monoclonal antibody fused with a truncated receptor binding domain of growth arrest-specific 6 (Gas6), a bridging molecule for the clearance of dead cells via TAM (TYRO3, AXL, and MERTK) receptors. This chimeric fusion protein (alpha A beta-Gas6) selectively eliminates A beta plaques through TAM receptor-dependent phagocytosis without inducing NF-kB-mediated inflammatory responses or reactive gliosis. Furthermore, alpha A beta-Gas6 can induce synergistic clearance of A beta by activating both microglial and astrocytic phagocytosis, resulting in better behavioral outcomes with substantially reduced synapse elimination and microhemorrhage in AD and cerebral amyloid angiopathy model mice compared with A beta antibody treatment. Our results suggest that alpha A beta-Gas6 could be a novel immunotherapeutic agent for AD that overcomes the side effects of conventional antibody therapy.
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NATURE MEDICINE, v.28, no.9, pp.1802 - 1812

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BS-Journal Papers(저널논문)
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