厄洛替尼是一种表皮生长因子受体（EGFR）抑制剂，经 FDA 批准用于治疗非小细胞肺癌（NSCLC）。包括 EGFR 在内的多种膜受体与 β 淀粉样蛋白 (Aβ) 相互作用，增加了厄洛替尼对阿尔茨海默病 (AD) 具有治疗作用的可能性。然而，厄洛替尼对AD小鼠模型中Aβ/tau相关病理学和认知功能的影响及其作用机制尚未得到详细研究。为了研究厄洛替尼对认知功能和AD病理学的影响，3至6-月龄 PS19 小鼠和 3 至 3.5 月龄 5xFAD 小鼠和 WT 小鼠每天注射载体（5% DMSO 10% PEG 20% Tween80 65% D.W.）或厄洛替尼（20 mg/kg，腹腔注射），持续 14 或21天。然后进行行为测试、高尔基体染色、免疫荧光染色、蛋白质印迹ELISA和实时PCR。我们发现厄洛替尼显着增强6个月大的P301S tau转基因（PS19）的短期空间记忆和树突棘形成。老鼠。重要的是，在 3 个月大和/或 6 个月大的婴儿中，厄洛替尼给药减少了 Ser202/Thr205 (AT8) 和 Thr231 (AT180) 的 tau 磷酸化，并进一步聚集成配对螺旋片段 (PHF) 和神经原纤维缠结 (NFT)。通过抑制 tau 激酶 DYRK1A 的表达来抑制老 PS19 小鼠。此外，厄洛替尼治疗可减少 6 个月大 PS19 小鼠的星形胶质细胞增生，并减少 PS19 小鼠原代星形胶质细胞 (PAC) 的促炎反应。在 3 至 3.5 个月大的 5xFAD 小鼠中，厄洛替尼治疗改善了短期空间记忆和海马树突棘数量，并减少了 Aβ 斑块沉积和 tau 蛋白过度磷酸化。此外，厄洛替尼治疗的 5xFAD 小鼠表现出星形胶质细胞活化的显着下调，并且用厄洛替尼处理 5xFAD 小鼠的 PAC 显着降低了 cxcl10（反应性星形胶质细胞标记物）和 gbp2（A1 星形胶质细胞标记物）mRNA 水平以及促炎细胞因子 mRNA 和蛋白质水平。综上所述，我们的结果表明，厄洛替尼可调节 tau/Aβ 诱导的 AD 病理、认知功能和 Aβ/tau 诱发的星形胶质细胞增生，因此可能成为改善 AD 症状的有效治疗药物。版权所有 © 2024 Lee, Hwang, Kim, Jo 、朴、郑、张、金、宋​​、锄。

Erlotinib is an epidermal growth factor receptor (EGFR) inhibitor that is approved by the FDA to treat non-small cell lung cancer (NSCLC). Several membrane receptors, including EGFR, interact with amyloid β (Aβ), raising the possibility that erlotinib could have therapeutic effects on Alzheimer's disease (AD). However, the effects of erlotinib on Aβ/tau-related pathology and cognitive function in mouse models of AD and its mechanisms of action have not been examined in detail.To investigate the effects of erlotinib on cognitive function and AD pathology, 3 to 6-month-old PS19 mice and 3 to 3.5-month-old 5xFAD mice and WT mice were injected with vehicle (5% DMSO + 10% PEG + 20% Tween80 + 65% D.W.) or erlotinib (20 mg/kg, i.p.) daily for 14 or 21 days. Then, behavioral tests, Golgi staining, immunofluorescence staining, western blotting ELISA, and real-time PCR were conducted.We found that erlotinib significantly enhanced short-term spatial memory and dendritic spine formation in 6-month-old P301S tau transgenic (PS19) mice. Importantly, erlotinib administration reduced tau phosphorylation at Ser202/Thr205 (AT8) and Thr231 (AT180) and further aggregation of tau into paired helical fragments (PHFs) and neurofibrillary tangles (NFTs) in 3-month-old and/or 6-month-old PS19 mice by suppressing the expression of the tau kinase DYRK1A. Moreover, erlotinib treatment decreased astrogliosis in 6-month-old PS19 mice and reduced proinflammatory responses in primary astrocytes (PACs) from PS19 mice. In 3- to 3.5-month-old 5xFAD mice, erlotinib treatment improved short-term spatial memory and hippocampal dendritic spine number and diminished Aβ plaque deposition and tau hyperphosphorylation. Furthermore, erlotinib-treated 5xFAD mice exhibited significant downregulation of astrocyte activation, and treating PACs from 5xFAD mice with erlotinib markedly reduced cxcl10 (reactive astrocyte marker) and gbp2 (A1 astrocyte marker) mRNA levels and proinflammatory cytokine mRNA and protein levels. Taken together, our results suggest that erlotinib regulates tau/Aβ-induced AD pathology, cognitive function, and Aβ/tau-evoked astrogliosis and therefore could be a potent therapeutic drug for ameliorating AD symptoms.Copyright © 2024 Lee, Hwang, Kim, Jo, Park, Jeong, Jang, Kim, Song and Hoe.