Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, Korea.
Medical Device Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu, Korea.
Aging Cell. 2021 Mar;20(3):e13332. doi: 10.1111/acel.13332. Epub 2021 Mar 11.
We previously demonstrated that ibrutinib modulates LPS-induced neuroinflammation in vitro and in vivo, but its effects on the pathology of Alzheimer's disease (AD) and cognitive function have not been investigated. Here, we investigated the effects of ibrutinib in two mouse models of AD. In 5xFAD mice, ibrutinib injection significantly reduced Aβ plaque levels by promoting the non-amyloidogenic pathway of APP cleavage, decreased Aβ-induced neuroinflammatory responses, and significantly downregulated phosphorylation of tau by reducing levels of phosphorylated cyclin-dependent kinase-5 (p-CDK5). Importantly, tau-mediated neuroinflammation and tau phosphorylation were also alleviated by ibrutinib injection in PS19 mice. In 5xFAD mice, ibrutinib improved long-term memory and dendritic spine number, whereas in PS19 mice, ibrutinib did not alter short- and long-term memory but promoted dendritic spinogenesis. Interestingly, the induction of dendritic spinogenesis by ibrutinib was dependent on the phosphorylation of phosphoinositide 3-kinase (PI3K). Overall, our results suggest that ibrutinib modulates AD-associated pathology and cognitive function and may be a potential therapy for AD.
我们之前的研究表明，依鲁替尼可调节 LPS 诱导的体外和体内神经炎症，但它对阿尔茨海默病（AD）的病理和认知功能的影响尚未被研究。在这里，我们研究了依鲁替尼在两种 AD 小鼠模型中的作用。在 5xFAD 小鼠中，依鲁替尼注射通过促进 APP 切割的非淀粉样蛋白途径显著降低 Aβ 斑块水平，降低 Aβ 诱导的神经炎症反应，并通过降低磷酸化周期蛋白依赖性激酶-5（p-CDK5）水平显著下调 tau 的磷酸化。重要的是，依鲁替尼注射还减轻了 PS19 小鼠中的 tau 介导的神经炎症和 tau 磷酸化。在 5xFAD 小鼠中，依鲁替尼改善了长期记忆和树突棘数量，而在 PS19 小鼠中，依鲁替尼没有改变短期和长期记忆，但促进了树突棘发生。有趣的是，依鲁替尼诱导的树突棘发生依赖于磷酸肌醇 3-激酶（PI3K）的磷酸化。总的来说，我们的结果表明，依鲁替尼可调节 AD 相关的病理和认知功能，可能是 AD 的一种潜在治疗方法。
