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-cyclohexene-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 the 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. In the present study, we investigated the inhibitory effect of K284-6111 on memory dysfunction and neuroinflammation in Tg2576 transgenic mice, and a 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 4 weeks to Tg2576 mice, followed by behavioral tests of water maze test, probe test, and passive avoidance test. Administration of K284-6111 alleviated memory impairment in Tg2576 mice and had the effect of reducing the 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 the 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 an inhibitory effect on the production of inflammatory proteins and cytokines, and on the phosphorylation of ERK and IκBα. These results suggest that K284-6111 could improve memory dysfunction by alleviating neuroinflammation through inhibiting CHI3L1 enhancing ERK-dependent PTX3 pathway.

中文翻译：

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K284-6111 通过抑制几丁质酶 3 样 1 调节 ERK 依赖性 PTX3 通路减轻 Tg2576 小鼠的记忆障碍和神经炎症

阿尔茨海默病 (AD) 是最普遍的神经退行性疾病之一，其特征是逐渐丧失记忆力和神经精神症状。我们之前已经证明了 2-({3-[2-(1-环己烯-1-基)乙基]-6,7-二甲氧基-4-氧代-3,4-二氢-2-喹唑啉基}硫烷基)- N-(4-乙基苯基)丁酰胺 (K284-6111) 是 CHI3L1 的抑制剂，对 Aβ 输注小鼠模型中的记忆障碍和 LPS 诱导的小鼠 BV-2 小胶质细胞和原代培养的星形胶质细胞中的神经炎症具有抑制作用。在本研究中，我们研究了 K284-6111 对 Tg2576 转基因小鼠记忆功能障碍和神经炎症的抑制作用，以及 CHI3L1 和 AD 的更详细的相关性。为了研究 K284-6111 对记忆功能障碍的影响，我们每天对 Tg2576 小鼠施用 K284-6111（3 毫克/千克，口服）4 周，其次是水迷宫测试、探针测试和被动回避测试的行为测试。K284-6111 的给药减轻了 Tg2576 小鼠的记忆障碍，并具有减少小鼠大脑中 Aβ 积累和神经炎症反应的作用。K284-6111 处理还选择性地使小鼠脑和 BV-2 细胞中的 ERK 和 NF-κB 通路失活，当 CHI3L1 过表达时，这些通路被激活。基于 Web 的基因网络分析和我们对 BV-2 细胞中基因表达水平的结果表明 CHI3L1 与 PTX3 密切相关。我们的结果表明，PTX3 的敲低对炎症蛋白和细胞因子的产生以及 ERK 和 IκBα 的磷酸化具有抑制作用。