Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
Institute of Pharmacology and Clinical Pharmacy, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
Int J Mol Sci. 2023 Jun 28;24(13):10810. doi: 10.3390/ijms241310810.
Tau protein aggregations are important contributors to the etiology of Alzheimer's disease (AD). Hydromethylthionine (HMT) is a potent inhibitor of tau aggregation in vitro and in vivo and is being developed as a possible anti-dementia medication. HMT was also shown to affect the cholinergic system and to interact with mitochondria. Here, we used tau-transgenic (L1 and L66) and wild-type NMRI mice that were treated with HMT, rivastigmine and memantine and with combinations thereof, for 2-4 weeks. We measured HMT concentrations in both brain homogenates and isolated mitochondria and concentrations of glucose, lactate and pyruvate in brain by microdialysis. In isolated brain mitochondria, we recorded oxygen consumption of mitochondrial complexes by respirometry. While rivastigmine and memantine lowered mitochondrial respiration, HMT did not affect respiration in wild-type animals and increased respiration in tau-transgenic L1 mice. Glucose and lactate levels were not affected by HMT administration. The presence of HMT in isolated mitochondria was established. In summary, traditional anti-dementia drugs impair mitochondrial function while HMT has no adverse effects on mitochondrial respiration in tau-transgenic mice. These results support the further development of HMT as an anti-dementia drug.
tau 蛋白聚集是阿尔茨海默病（AD）发病机制的重要因素。羟甲基硫氨酸（HMT）是体外和体内 tau 聚集的有效抑制剂，目前正在开发作为一种潜在的抗痴呆药物。HMT 还被证明可以影响胆碱能系统并与线粒体相互作用。在这里，我们使用了经过 HMT、利伐斯的明和盐酸美金刚处理 2-4 周的 tau 转基因（L1 和 L66）和野生型 NMRI 小鼠，并与它们的组合进行了研究。我们通过微透析测量了脑匀浆和分离的线粒体中的 HMT 浓度以及大脑中的葡萄糖、乳酸和丙酮酸浓度。在分离的脑线粒体中，我们通过呼吸计记录了线粒体复合物的耗氧量。虽然利伐斯的明和盐酸美金刚降低了线粒体呼吸，但 HMT 对野生型动物的呼吸没有影响，反而增加了 tau 转基因 L1 小鼠的呼吸。HMT 给药不会影响葡萄糖和乳酸水平。在分离的线粒体中存在 HMT 得到了证实。总之，传统的抗痴呆药物会损害线粒体功能，而 HMT 对 tau 转基因小鼠的线粒体呼吸没有不良影响。这些结果支持进一步开发 HMT 作为一种抗痴呆药物。
