Florey Institute of Neuroscience and Mental Health , Parkville, Melbourne , Victoria 3052 , Australia.
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science , La Trobe University , Melbourne , Victoria 3086 , Australia.
ACS Chem Neurosci. 2018 Nov 21;9(11):2731-2740. doi: 10.1021/acschemneuro.8b00161. Epub 2018 Jul 3.
Alzheimer's disease (AD) is the leading cause of dementia worldwide accounting for around 70% of all cases. There is currently no treatment for AD beyond symptom management and attempts at developing disease-modifying therapies have yielded very little. These strategies have traditionally targeted the peptide Aβ, which is thought to drive pathology. However, the lack of clinical translation of these Aβ-centric strategies underscores the need for diverse treatment strategies targeting other aspects of the disease. Metal dyshomeostasis is a common feature of several neurodegenerative diseases such as AD, Parkinson's disease, and frontotemporal dementia, and manipulation of metal homeostasis has been explored as a potential therapeutic avenue for these diseases. The copper ionophore glyoxalbis-[N4-methylthiosemicarbazonato]Cu(II) (Cu(gtsm)) has previously been shown to improve the cognitive deficits seen in an AD animal model; however, the molecular mechanism remained unclear. Here we report that the treatment of two animal tauopathy models (APP/PS1 and rTg4510) with Cu(gtsm) recovers the cognitive deficits seen in both neurodegenerative models. In both models, markers of tau pathology were significantly reduced with Cu(gtsm) treatment, and in the APP/PS1 model, the levels of Aβ remained unchanged. Analysis of tau kinases (GSK3β and CDK5) revealed no drug induced changes; however, both models exhibited a significant increase in the levels of the structural subunit of the tau phosphatase, PP2A. These findings suggest that targeting the tau phosphatase PP2A has therapeutic potential for preventing memory impairments and reducing the tau pathology seen in AD and other tauopathies.
阿尔茨海默病（AD）是全球痴呆症的主要病因，约占所有病例的 70%。目前，AD 除了症状管理之外，还没有治疗方法，试图开发疾病修饰疗法的效果非常有限。这些策略传统上针对肽 Aβ，认为它是导致病理的原因。然而，这些以 Aβ 为中心的策略缺乏临床转化，突显了需要针对疾病的其他方面制定多样化的治疗策略。金属动态失衡是几种神经退行性疾病（如 AD、帕金森病和额颞叶痴呆）的共同特征，因此，操纵金属动态平衡已被探索为这些疾病的潜在治疗途径。铜离子载体乙二醛双[N4-甲基硫代半缩醛]Cu(II)（Cu(gtsm)）先前已被证明可改善 AD 动物模型中的认知缺陷；然而，其分子机制仍不清楚。在这里，我们报告说，用 Cu(gtsm)治疗两种动物 tau 病模型（APP/PS1 和 rTg4510）可恢复两种神经退行性模型中观察到的认知缺陷。在两种模型中，tau 病理学标志物的水平均显著降低，而在用 Cu(gtsm)治疗后，APP/PS1 模型中的 Aβ 水平保持不变。对 tau 激酶（GSK3β 和 CDK5）的分析表明，没有药物诱导的变化；然而，两种模型均表现出 tau 磷酸酶的结构亚基 PP2A 的水平显著增加。这些发现表明，靶向 tau 磷酸酶 PP2A 具有治疗潜力，可以预防记忆障碍并减少 AD 和其他 tau 病中观察到的 tau 病理学。
