K284-6111 Alleviates Memory Impairment and Neuroinflammation in Tg2576 Mice by Inhibition of Chitinase-3-like 1 Regulating ERK Dependent PTX3 Pathway

Abstract

Background Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by gradual memory loss and neuropsychiatric symptoms. We have previously demonstrated that the 2-({3-[2-(1-Cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111), the inhibitor of CHI3L1, has an inhibitory effect on memory impairment in Αβ infusion mouse model and on LPS-induced neuroinflammation in the murine BV-2 microglia and primary cultured astrocyte. Methods In the present study, we investigated that the inhibitory effect of K284-6111 on memory dysfunction and neuroinflammation in Tg2576 transgenic mice, and more detailed correlation of CHI3L1 and AD. To investigate the effects of K284-6111 on memory dysfunction, we administered K284-6111 (3 mg/kg, p.o.) daily for four weeks to Tg2576, followed by behavioral tests of water maze test, probe test, and passive avoidance test.Results Administration of K284-6111 alleviated memory impairment in Tg2576 mice and had the effect of reducing accumulation of Aβ and neuroinflammatory responses in the mouse brain. K284-6111 treatment also selectively inactivated ERK and NF-κB pathways, which were activated when CHI3L1 was overexpressed, in mouse brain and in BV-2 cells. Web-based gene network analysis and our results of gene expression level in BV-2 cells showed that CHI3L1 is closely correlated with PTX3. Our result revealed that knockdown of PTX3 has inhibitory effect on the production of inflammatory proteins and cytokines, and on the phosphorylation of ERK and IκBα.Conclusion These results suggest that K284-6111 could improve memory dysfunction by alleviating neuroinflammation through inhibiting CHI3L1 through blocking ERK dependent PTX3 pathway.

Potential role of chitinase‐3‐like protein 1 (CHI3L1/YKL‐40) in neurodegeneration and Alzheimer's disease

“…The CHI3L1 inhibitor reduced the number of iNOS, COX-2, GFAP, and Iba-1 positive cells, indicating an inhibition of microglial and astrocytic activation, and also decreased the levels of TNF-α, IL-1β, and IL-6 in the brains of the Tg2576 transgenic mice. 92 These results are consistent with the group's previous results in the Aβ 1-42 -induced AD model.…”

“…91 Furthermore, in the brain, the same CHI3L1 inhibitor decreased the M1 markers TNF, IL-1β, IL-6, and CD86, while CHI3L1 overexpression increased the expression of these M1 markers. 92 Conversely, M2 markers such as Arg1, Mrc1, TGF-β, and IL-10 were unaffected by the inhibition of CHI3L1. 92 This indicates that CHI3L1 may drive the activation of microglia to an M1, pro-inflammatory phenotype.…”

“…92 Conversely, M2 markers such as Arg1, Mrc1, TGF-β, and IL-10 were unaffected by the inhibition of CHI3L1. 92 This indicates that CHI3L1 may drive the activation of microglia to an M1, pro-inflammatory phenotype. However, other research using microglia isolated from middle cerebral artery occlusion-injured CHI3L1 knockout mice describe opposite results where CHI3L1 knockout increased the M1 markers iNOS, CD86, IL-1β, and IL-6, and decreased the M2 markers Arg1, Mrc1, IL-10, and IL-4Rα.…”

Pentraxin 3-Induced Fibrotic Scar Formation via Astrocytic Cebpd activation after Spinal Cord Injury

“…6). Most importantly, increased Ptx3 secretion may correlate with neurodegenerative disease progression, such as Alzheimer's disease and Parkinson's disease 7,24,25 . Thus, Ptx3 may act as therapeutic target for neurodegenerative disease and spinal cord injury, and support the ongoing development of synthetic peptide RI37 for the treatment of spinal cord injury.…”

“…Pentraxin-3 (Ptx3) belongs to the long pentraxin family and is expressed in a variety of cell type, especially astrocyte in central nervous system 7,8 . Previous study showed that astrocytic Cebpd can activate Ptx3 expression that inhibit macrophage-mediated phagocytosis 9 .…”