Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran.
Department of Biology, Faculty of Sciences, University of Zabol, Zabol, Iran.
Metab Brain Dis. 2021 Apr;36(4):669-683. doi: 10.1007/s11011-021-00679-7. Epub 2021 Feb 6.
Tauopathies belong to a heterogeneous class of neuronal diseases resulting in the metabolic disturbance. A disulfide natural compound of Alpha-Lipoic acid (ALA) has shown numerous pharmacologic, antioxidant, and neuroprotective activities under neuropathological conditions. The aim of this study was to investigate the neuroprotective effects of ALA on the tauopathy-induced oxidative disturbance and behavioral deficits. The transgenic Drosophila model of tauopathy induced by human tau using GAL4/UAS system and effects of ALA (0.001, 0.005, and 0.025 % w/w of diet) on the neuropathology of tau in younger (20 days) and older (30 days) adults were investigated via biochemical, molecular, behavioral and in-situ tissue analyses. Expression of apoptosis-related proteins involving Drosophila Cyt-c-d (trigger of intrinsic apoptosis) and DrICE (effector caspase) were upregulated in both ages (20 and 30 days) and DIAP1 (caspase inhibitor) has reduced only in older model flies compared to the controls. Remarkably, all doses of ALA increased DIAP1 and glutathione (GSH) as well as reducing Cyt-c-d and lipid peroxidation (LPO) in the younger flies compared to the model flies. Moreover, the higher doses of ALA were able to decrease thiol concentrations, to increase total antioxidant capacity, and to improve the behavioral deficits (locomotor function, olfactory memory, and ethanol sensitivity) in the younger flies. On the other hand, only a higher dose of ALA was able to decrease DrICE, Cyt-c-d, LPO, and thiol as well as increasing antioxidant capacity and decreasing ethanol sensitivity (ST50, RT50) in the older flies. TUNEL assay showed that all doses of ALA could potentially increase the DIAP1/DrICE ratio and exert anti-apoptotic effects on younger, but not on the older adults. Furthermore, data obtained from the in-situ ROS assay confirmed that only a higher dose of ALA significantly decreased the ROS level at both ages. Our data showed that an effective neuroprotective dose of ALA and its mechanism of action on this model of tauopathy could potentially be influenced by longevity. Moreover, it was shown that ALA prevents apoptosis and decreases the redox homeostasis, and this partially explains the mechanism by which ALA diminishes behavioral deficits.
tau 病属于导致代谢紊乱的神经元疾病的异质类。硫辛酸（ALA）的一种二硫天然化合物在神经病理学条件下显示出许多药理、抗氧化和神经保护活性。本研究旨在研究 ALA 对 tau 病引起的氧化干扰和行为缺陷的神经保护作用。使用 GAL4/UAS 系统诱导人 tau 的转 tau 果蝇模型和 ALA（饮食中 0.001、0.005 和 0.025%w/w）对年轻（20 天）和年老（30 天）成虫 tau 神经病理学的影响通过生化、分子、行为和原位组织分析进行了研究。凋亡相关蛋白的表达涉及果蝇 Cyt-c-d（内在凋亡的触发物）和 DrICE（效应半胱天冬酶）在两个年龄（20 和 30 天）都上调，而 DIAP1（半胱天冬酶抑制剂）仅在年老模型果蝇中与对照相比降低。值得注意的是，与模型果蝇相比，ALA 的所有剂量都增加了年轻果蝇中的 DIAP1 和谷胱甘肽（GSH），并降低了 Cyt-c-d 和脂质过氧化（LPO）。此外，较高剂量的 ALA 能够降低巯基浓度、增加总抗氧化能力并改善年轻果蝇的行为缺陷（运动功能、嗅觉记忆和乙醇敏感性）。另一方面，只有较高剂量的 ALA 能够降低 DrICE、Cyt-c-d、LPO 和巯基，增加抗氧化能力并降低老年果蝇的乙醇敏感性（ST50、RT50）。TUNEL 测定表明，ALA 的所有剂量都可能增加 DIAP1/DrICE 比值，并对年轻果蝇发挥抗凋亡作用，但对老年成虫没有作用。此外，来自原位 ROS 测定的数据证实，只有较高剂量的 ALA 能够在两个年龄都显著降低 ROS 水平。我们的数据表明，ALA 的有效神经保护剂量及其在这种 tau 病模型中的作用机制可能受到寿命的影响。此外，研究表明 ALA 可预防细胞凋亡并降低氧化还原稳态，这部分解释了 ALA 减轻行为缺陷的机制。
