澳门大学TKin Yip Tam等研究人员合作通过三重靶向抑制胆碱酯酶、淀粉样聚集和GSK3β，改善三重转基因小鼠阿尔茨海默病的认知缺陷和神经病理。相关论文于2025年2月5日在线发表在《神经科学通报》杂志上。

研究人员报告了一种新型抑制剂——化合物44，用于同时靶向胆碱酯酶、淀粉样β（Aβ）聚集和糖原合成酶激酶3β（GSK-3β），旨在实现阿尔茨海默病（AD）治疗中的症状缓解和疾病修改。研究人员发现，化合物44对所有目标均具有良好的抑制作用，其IC₅₀值为亚微摩尔或更低，在细胞模型中具有显著的神经保护作用，并在三重转基因AD（3×Tg AD）小鼠模型中显著改善认知缺陷。

此外，研究人员还显示，化合物44通过抑制GSK-3β，诱导转录因子EB的核转位，调节自噬，增强溶酶体的生成和自噬流，从而减轻淀粉样负担和tau病理，并缓解疾病表型。这些结果表明，通过化合物44进行三重靶向抑制可能是一种有前景的策略，有望为AD的有效治疗方法的开发提供新的方向。

据悉，AD是21世纪最紧迫的医学挑战之一，影响着数百万人。不幸的是，AD的病因机制尚未完全了解，目前的药物治疗选择有限。

附：英文原文

Title: Triple-Target Inhibition of Cholinesterase, Amyloid Aggregation, and GSK3β to Ameliorate Cognitive Deficits and Neuropathology in the Triple-Transgenic Mouse Model of Alzheimer’s Disease

Author: He, Junqiu, Sun, Shan, Wang, Hongfeng, Ying, Zheng, Tam, Kin Yip

Issue&Volume: 2025-02-05

Abstract: Alzheimer’s disease (AD) poses one of the most urgent medical challenges in the 21st century as it affects millions of people. Unfortunately, the etiopathogenesis of AD is not yet fully understood and the current pharmacotherapy options are somewhat limited. Here, we report a novel inhibitor, Compound 44, for targeting cholinesterases, amyloid-β (Aβ) aggregation, and glycogen synthase kinase 3β (GSK-3β) simultaneously with the aim of achieving symptomatic relief and disease modification in AD therapy. We found that Compound 44 had good inhibitory effects on all intended targets with IC50s of submicromolar or better, significant neuroprotective effects in cell models, and beneficial improvement of cognitive deficits in the triple transgenic AD (3×Tg AD) mouse model. Moreover, we showed that Compound 44 acts as an autophagy regulator by inducing nuclear translocation of transcription factor EB through GSK-3β inhibition, enhancing the biogenesis of lysosomes and elevating autophagic flux, thus ameliorating the amyloid burden and tauopathy, as well as mitigating the disease phenotype. Our results suggest that triple-target inhibition via Compound 44 could be a promising strategy that may lead to the development of effective therapeutic approaches for AD.

DOI: 10.1007/s12264-025-01354-y

Source: https://link.springer.com/article/10.1007/s12264-025-01354-y