Iyaswamy Ashok, Wang Xueli, Krishnamoorthi Senthilkumar, Kaliamoorthy Venkatapathy, Sreenivasmurthy Sravan G, Kumar Durairajan Siva Sundara, Song Ju-Xian, Tong Benjamin Chun-Kit, Zhu Zhou, Su Cheng-Fu, Liu Jia, Cheung King-Ho, Lu Jia-Hong, Tan Jie-Qiong, Li Hung Wing, Wong Man Shing, Li Min
Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China.
Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR, China.
Redox Biol. 2022 May;51:102280. doi: 10.1016/j.redox.2022.102280. Epub 2022 Mar 8.
Accumulation of amyloid-β (Aβ) oligomers and phosphorylated Tau aggregates are crucial pathological events or factors that cause progressive neuronal loss, and cognitive impairments in Alzheimer's disease (AD). Current medications for AD have failed to halt, much less reverse this neurodegenerative disorder; therefore, there is an urgent need for the development of effective and safe drugs for AD therapy. In the present study, the in vivo therapeutic efficacy of an Aβ-oligomer-targeted fluorescent probe, F-SLOH, was extensively investigated in 5XFAD and 3XTg-AD mouse models. We have shown that F-SLOH exhibits an efficient inhibitory activity against Aβ aggregation in vivo, and acts as an effective theranostic agent for the treatment of multiple neuropathological changes in AD mouse models. F-SLOH has been found to significantly reduce not only the levels of Aβ oligomers, Tau aggregates and plaques but also the levels of amyloid precursor protein (APP) and its metabolites via autophagy lysosomal degradation pathway (ALP) in the brains of 5XFAD and 3XTg-AD mice. It also reduces astrocyte activation and microgliosis ultimately alleviating neuro-inflammation. Furthermore, F-SLOH mitigates hyperphosphorylated Tau aggregates, synaptic deficits and ameliorates synaptic memory function, and cognitive impairment in AD mouse models. The mechanistic studies have shown that F-SLOH promotes the clearance of C-terminal fragment 15 (CTF15) of APP and Paired helical filaments of Tau (PHF1) in stable cell models via the activation of transcription factor EB (TFEB). Moreover, F-SLOH promotes ALP and lysosomal biogenesis for the clearance of soluble, insoluble Aβ, and phospho Tau. Our results unambiguously reveal effective etiological capabilities of theranostic F-SLOH to target and intervene multiple neuropathological changes in AD mouse models. Therefore, F-SLOH demonstrates tremendous therapeutic potential for treating AD in its early stage.
淀粉样β（Aβ）寡聚体和磷酸化 Tau 聚集体的积累是导致阿尔茨海默病（AD）中神经元进行性丧失和认知障碍的关键病理事件或因素。目前用于 AD 的药物未能阻止，更不用说逆转这种神经退行性疾病；因此，迫切需要开发有效且安全的 AD 治疗药物。在本研究中，在 5XFAD 和 3XTg-AD 小鼠模型中广泛研究了一种靶向 Aβ 寡聚体的荧光探针 F-SLOH 的体内治疗效果。我们已经表明，F-SLOH 在体内对 Aβ 聚集表现出有效的抑制活性，并作为一种有效的治疗诊断剂用于治疗 AD 小鼠模型中的多种神经病理变化。已发现 F-SLOH 不仅能显著降低 5XFAD 和 3XTg-AD 小鼠大脑中 Aβ 寡聚体、Tau 聚集体和斑块的水平，还能通过自噬溶酶体降解途径（ALP）降低淀粉样前体蛋白（APP）及其代谢产物的水平。它还能减少星形胶质细胞活化和小胶质细胞增生，最终减轻神经炎症。此外，F-SLOH 减轻了过度磷酸化的 Tau 聚集体、突触缺陷，并改善了 AD 小鼠模型中的突触记忆功能和认知障碍。机制研究表明，F-SLOH 通过激活转录因子 EB（TFEB）促进稳定细胞模型中 APP 的 C 末端片段 15（CTF15）和 Tau 的双螺旋丝（PHF1）的清除。此外，F-SLOH 促进 ALP 和溶酶体生物合成以清除可溶性、不溶性 Aβ 和磷酸化 Tau。我们的结果明确揭示了治疗诊断剂 F-SLOH 在 AD 小鼠模型中靶向和干预多种神经病理变化的有效病因学能力。因此，F-SLOH 在 AD 早期治疗中显示出巨大的治疗潜力。
