# CHI3L1 monoclonal antibody therapy mitigates cognitive impairment by inhibiting neuroinflammation through ERK and NF-κB pathway in Tg2576 mice

## TL;DR

A CHI3L1 monoclonal antibody reduces cognitive decline in Alzheimer's mice by suppressing brain inflammation and amyloid buildup.

## Contribution

A novel CHI3L1 monoclonal antibody (H1) is shown to cross the blood-brain barrier and reduce AD-related neuroinflammation and memory impairment.

## Key findings

- H1 treatment improved cognitive function and reduced amyloid deposition in Tg2576 mice.
- H1 inhibited ERK and NF-κB pathways and suppressed M1 microglial markers.
- H1 reduced HAX1 levels, which are linked to CHI3L1 and Aβ-induced inflammation.

## Abstract

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 1 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 neuroinflamma.