한빛사논문
- 조회723
Hyuncheol Jung1,4, Se Young Lee1,4, Seongjoon Lim 1, Hyeong Ryeol Choi1, Yeseong Choi1, Minjin Kim1, Segi Kim1, Yujean Lee1, Kyung Ho Han1,3, Won-Suk Chung 1,2,* and Chan Hyuk Kim 1,*
1Department of Biological Sciences Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. 2KAIST Stem Cell Center, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. 3Present address: Department of Biological Sciences and Biotechnology, Hannam University, Daejeon, Republic of Korea. 4These authors contributed equally: Hyuncheol Jung, Se Young Lee.
*Corresponding author.
Abstract
Clearing amyloid-β (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 patients with AD, 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. Here, we develop a phagocytosis inducer for Aβ consisting of a single-chain variable fragment of an Aβ-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 (αAβ–Gas6) selectively eliminates Aβ plaques through TAM 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 and microhemorrhage in AD and cerebral amyloid angiopathy model mice compared with Aβ antibody treatment. Our results suggest that αAβ–Gas6 could be a novel immunotherapeutic agent for AD that overcomes the side effects of conventional antibody therapy.
논문정보
- Research article
- 2022년 08월 (BRIC 등록일 2022-08-24)
- 국내 연구진
- 바이오·의료융합 > 바이오센싱 및 나노바이오물질
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