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

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dc.contributor.authorJung, Hyuncheolko
dc.contributor.authorLee, Se Youngko
dc.contributor.authorLim, Seongjoonko
dc.contributor.authorChoi, Hyeong Ryeolko
dc.contributor.authorChoi, Yeseongko
dc.contributor.authorKim, Minjinko
dc.contributor.authorKim, Segiko
dc.contributor.authorLee, Yujeanko
dc.contributor.authorHan, Kyung Hoko
dc.contributor.authorChung, Won-Sukko
dc.contributor.authorKim, Chan Hyukko
dc.date.accessioned2022-10-05T07:00:44Z-
dc.date.available2022-10-05T07:00:44Z-
dc.date.created2022-08-15-
dc.date.created2022-08-15-
dc.date.issued2022-09-
dc.identifier.citationNATURE MEDICINE, v.28, no.9, pp.1802 - 1812-
dc.identifier.issn1078-8956-
dc.identifier.urihttp://hdl.handle.net/10203/298832-
dc.description.abstractAn 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.-
dc.languageEnglish-
dc.publisherNATURE PORTFOLIO-
dc.titleAnti-inflammatory clearance of amyloid-beta by a chimeric Gas6 fusion protein-
dc.typeArticle-
dc.identifier.wosid000836112500001-
dc.identifier.scopusid2-s2.0-85135574586-
dc.type.rimsART-
dc.citation.volume28-
dc.citation.issue9-
dc.citation.beginningpage1802-
dc.citation.endingpage1812-
dc.citation.publicationnameNATURE MEDICINE-
dc.identifier.doi10.1038/s41591-022-01926-9-
dc.contributor.localauthorChung, Won-Suk-
dc.contributor.localauthorKim, Chan Hyuk-
dc.contributor.nonIdAuthorKim, Minjin-
dc.contributor.nonIdAuthorLee, Yujean-
dc.description.isOpenAccessN-
dc.type.journalArticleArticle-
dc.subject.keywordPlusTAU-MEDIATED NEURODEGENERATION-
dc.subject.keywordPlusMOUSE MODEL-
dc.subject.keywordPlusPHAGOCYTOSIS-
dc.subject.keywordPlusRECEPTORS-
dc.subject.keywordPlusMYELINOGENESIS-
dc.subject.keywordPlusINFLAMMATION-
dc.subject.keywordPlusMODULATION-
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