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

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Jung H, Lee SY, Lim S, Choi HR, Choi Y, Kim M, Kim S, Lee Y, Han KH, Chung WS, Kim CH

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

Nat Med. 2022 Sep;28(9):1802-1812. doi: 10.1038/s41591-022-01926-9. Epub 2022 Aug 4.

PubMed ID
35927581 [ View in PubMed
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Abstract

Clearing amyloid-beta (Abeta) through immunotherapy is one of the most promising therapeutic approaches to Alzheimer's disease (AD). Although several monoclonal antibodies against Abeta have been shown to substantially reduce Abeta burden in patients with AD, their effects on improving cognitive function remain marginal. In addition, a significant portion of patients treated with Abeta-targeting antibodies experience brain edema and microhemorrhage associated with antibody-mediated Fc receptor activation in the brain. Here, we develop a phagocytosis inducer for Abeta consisting of a single-chain variable fragment of an Abeta-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 (alphaAbeta-Gas6) selectively eliminates Abeta plaques through TAM receptor-dependent phagocytosis without inducing NF-kB-mediated inflammatory responses or reactive gliosis. Furthermore, alphaAbeta-Gas6 can induce synergistic clearance of Abeta 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 Abeta antibody treatment. Our results suggest that alphaAbeta-Gas6 could be a novel immunotherapeutic agent for AD that overcomes the side effects of conventional antibody therapy.

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