ORIGINAL RESEARCH article
Front. Mol. Neurosci.
Sec. Brain Disease Mechanisms
This article is part of the Research TopicEmerging Mechanisms in Neurodegenerative Disease Pathogenesis: Vertebrate and Invertebrate Model OrganismsView all 3 articles
CHI3L1 monoclonal antibody therapy mitigates cognitive impairment by inhibiting neuroinflammation through ERK and NF-κB pathway in Tg2576 mice
Provisionally accepted
Hyeon Joo Ham
Seung Sik ParkTae Hun KimDong Ju Son
Ji-Hun KimKey-Hwan LimHanseul ParkHye Jin Lee
Jaesuk YunSang-Bae HanMin Ki Choi*
Jin Tae Hong*- Chungbuk National University, Cheongju, Republic of Korea
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Alzheimer's disease (AD) is neurodegenerative disorder characterized by chronic inflammation in the brain. Chitinase-3-like 1 (CHI3L1), a secreted glycoprotein that is upregulated in a variety of diseases with chronic inflammation, represents a promising target for AD. Here, we studied the inhibitory effect of a novel CHI3L1 monoclonal antibody (H1) on memory impairment and neuroinflammation in Tg2576 transgenic mice. H1 was shown to cross the blood-brain barrier selectively, as confirmed by fluorescence imaging. Tg2576 mice were administered H1 (2 mg/kg, i.v., weekly for one month), and cognitive functions were assessed through behavioral tests. H1 treatment alleviated memory impairment and reduced amyloid deposition and neuroinflammation both in Tg2576 mice and Aβ-induced BV-2 microglial cells. Mechanistically, H1 inhibited the ERK and NF-κB signaling pathways and suppressed M1 microglial marker expression. Global proteomic analysis and gene expression profiling in BV-2 cells and Tg2576 mouse brains revealed a strong association between CHI3L1 and HAX1 expression. H1 therapy significantly reduced HAX1 levels in both in vivo and in vitro models. Moreover, HAX1 induction by Aβ or CHI3L1 was blocked by an NF-κB inhibitor. These findings suggest that CHI3L1 monoclonal antibody therapy may attenuate cognitive decline in AD by modulating neuroinflammation.
Keywords: Alzheimer's disease, Antibody therapy, CHI3L1, HAX1, Neuroinflammation, NF-κB
Received: 19 Oct 2025; Accepted: 11 Dec 2025.
Copyright: © 2025 Ham, Park, Kim, Son, Kim, Lim, Park, Lee, Yun, Han, Choi and Hong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Min Ki Choi
Jin Tae Hong
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