Current Alzheimer Research ( IF 1.8 ) Pub Date : 2020-02-29 , DOI: 10.2174/1567205017666200224120926 Gernot Riedel 1 , Jochen Klein 2 , Grazyna Niewiadomska 3 , Constantin Kondak 1, 2 , Karima Schwab 4 , Dilyara Lauer 4 , Mandy Magbagbeolu 4 , Marta Steczkowska 5 , Maciej Zadrozny 5 , Malgorzata Wydrych 5 , Anna Cranston 1 , Valeria Melis 1 , Renato X Santos 1 , Franz Theuring 4 , Charles R Harrington 1, 6 , Claude M Wischik 1, 6
Background: Symptomatic treatments of Alzheimer’s Disease (AD) with cholinesterase inhibitors and/or memantine are relatively ineffective and there is a need for new treatments targeting the underlying pathology of AD. In most of the failed disease-modifying trials, patients have been allowed to continue taking symptomatic treatments at stable doses, under the assumption that they do not impair efficacy. In recently completed Phase 3 trials testing the tau aggregation inhibitor leuco-methylthioninium bis (hydromethanesulfonate) (LMTM), we found significant differences in treatment response according to whether patients were taking LMTM either as monotherapy or as an add-on to symptomatic treatments.
Methods: We have examined the effect of either LMTM alone or chronic rivastigmine prior to LMTM treatment of tau transgenic mice expressing the short tau fragment that constitutes the tangle filaments of AD. We have measured acetylcholine levels, synaptosomal glutamate release, synaptic proteins, mitochondrial complex IV activity, tau pathology and Choline Acetyltransferase (ChAT) immunoreactivity. Results: LMTM given alone increased hippocampal Acetylcholine (ACh) levels, glutamate release from synaptosomal preparations, synaptophysin levels in multiple brain regions and mitochondrial complex IV activity, reduced tau pathology, partially restored ChAT immunoreactivity in the basal forebrain and reversed deficits in spatial learning. Chronic pretreatment with rivastigmine was found to reduce or eliminate almost all these effects, apart from a reduction in tau aggregation pathology. LMTM effects on hippocampal ACh and synaptophysin levels were also reduced in wild-type mice. Conclusion: The interference with the pharmacological activity of LMTM by a cholinesterase inhibitor can be reproduced in a tau transgenic mouse model and, to a lesser extent, in wild-type mice. Long-term pretreatment with a symptomatic drug alters a broad range of brain responses to LMTM across different transmitter systems and cellular compartments at multiple levels of brain function. There is, therefore, no single locus for the negative interaction. Rather, the chronic neuronal activation induced by reducing cholinesterase function produces compensatory homeostatic downregulation in multiple neuronal systems. This reduces a broad range of treatment responses to LMTM associated with a reduction in tau aggregation pathology. Since the interference is dictated by homeostatic responses to prior symptomatic treatment, it is likely that there would be similar interference with other drugs tested as add-on to the existing symptomatic treatment, regardless of the intended therapeutic target or mode of action. The present findings outline key results that now provide a working model to explain interference by symptomatic treatment.中文翻译：
在Tau转基因小鼠模型中抗胆碱酯酶干扰Tau聚集抑制剂活性的机制。
背景：用胆碱酯酶抑制剂和/或美金刚对症治疗阿尔茨海默氏病（AD）相对无效，因此需要针对AD潜在病理学的新疗法。在大多数失败的疾病缓解试验中，假设患者不损害疗效，则允许他们继续以稳定剂量接受对症治疗。在最近完成的测试tau聚集抑制剂无色-甲硫基双（氢甲基磺酸盐）（LMTM）的3期试验中，我们发现根据患者是否将LMTM作为单一疗法还是对症治疗的补充，治疗反应存在显着差异。
方法：我们在LMTM治疗表达构成AD缠结丝的短tau片段的tau转基因小鼠之前，已经检查了单独的LMTM或慢性卡巴拉汀的作用。我们测量了乙酰胆碱水平，突触体谷氨酸释放，突触蛋白，线粒体复合物IV活性，tau病理学和胆碱乙酰转移酶（ChAT）免疫反应性。结果：单独给予LMTM可增加海马乙酰胆碱（ACh）水平，突触体制剂中的谷氨酸释放，多个脑区的突触素水平和线粒体复合物IV活性，tau病理学降低，基底前脑中的ChAT免疫反应性部分恢复以及空间学习的逆转。除减少tau聚集病理外，发现用rivastigmine进行的慢性预处理可减少或消除几乎所有这些影响。在野生型小鼠中，LMTM对海马ACh和突触素水平的影响也降低了。结论：胆碱酯酶抑制剂对LMTM药理活性的干扰可以在tau转基因小鼠模型中复制，而在较小程度上，可以在野生型小鼠中复制。对症药物的长期预处理会在多种脑功能水平上，跨越不同的递质系统和细胞区室，改变对LMTM的多种大脑反应。因此，没有任何一个消极相互作用的场所。而是，通过降低胆碱酯酶功能诱导的慢性神经元活化在多个神经元系统中产生代偿性稳态下调。这降低了对LMTM的多种治疗反应，从而降低了tau聚集病理。由于干扰是由对先前对症治疗的稳态反应决定的，不管预期的治疗靶点或作用方式如何，作为对现有对症治疗的附加药物测试的其他药物可能会有类似的干扰。目前的发现概述了关键结果，这些结果现在提供了一种工作模型来解释对症治疗的干扰。
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