The pathological misfolding and aggregation of the microtubule associated protein tau (MAPT), a full length Tau2N4R with 441aa, is considered the principal disease relevant constituent in tauopathies including Alzheimer’s disease (AD) with an imbalanced ratio in 3R/4R isoforms. The exact cellular fluid composition, properties, and changes that coincide with tau misfolding, seed formation, and propagation events remain obscure. The proteostasis network, along with the associated osmolytes, is responsible for maintaining the presence of tau in its native structure or dealing with misfolding. In this study, for the first time, the roles of natural brain osmolytes are being investigated for their potential effects on regulating the conformational stability of the tau monomer (tauM) and its propensity to aggregate or disaggregate. Herein, the effects of physiological osmolytes myo-inositol, taurine, trimethyl amine oxide (TMAO), betaine, sorbitol, glycerophosphocholine (GPC), and citrulline on tau’s aggregation state were investigated. The overall results indicate the ability of sorbitol and GPC to maintain the monomeric form and prevent aggregation of tau, whereas myo-inositol, taurine, TMAO, betaine, and citrulline promote tau aggregation to different degrees, as revealed by protein morphology in atomic force microscopy images. Biochemical and biophysical methods also revealed that tau proteins adopt different conformations under the influence of these osmolytes. TauM in the presence of all osmolytes expressed no toxicity when tested by a lactate dehydrogenase assay. Investigating the conformational stability of tau in the presence of osmolytes may provide a better understanding of the complex nature of tau aggregation in AD and the protective and/or chaotropic nature of osmolytes.

中文翻译：

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天然渗透剂对重组 Tau 单体的影响：寡聚和聚集的倾向

微管相关蛋白 tau (MAPT)（一种具有 441 个氨基酸的全长 Tau2N4R）的病理性错误折叠和聚集被认为是 tau 蛋白病的主要疾病相关成分，包括阿尔茨海默病 (AD)，其 3R/4R 同工型比例不平衡。与 tau 蛋白错误折叠、种子形成和繁殖事件相一致的确切细胞液成分、性质和变化仍然不清楚。蛋白质稳态网络以及相关的渗透剂负责维持 tau 蛋白的天然结构或处理错误折叠。在这项研究中，首次研究了天然脑渗透剂对调节 tau 单体 (tauM) 构象稳定性及其聚集或解聚倾向的潜在影响。在此，研究了生理渗透剂肌醇、牛磺酸、三甲胺氧化物（TMAO）、甜菜碱、山梨醇、甘油磷酸胆碱（GPC）和瓜氨酸对 tau 聚集状态的影响。总体结果表明，山梨醇和 GPC 能够维持单体形式并防止 tau 聚集，而肌醇、牛磺酸、TMAO、甜菜碱和瓜氨酸不同程度地促进 tau 聚集，如原子力显微镜中蛋白质形态所揭示的那样图片。生化和生物物理方法还表明，tau 蛋白在这些渗透剂的影响下采用不同的构象。当通过乳酸脱氢酶测定进行测试时，在所有渗透剂存在下，TauM 均未表现出毒性。研究渗透剂存在下 tau 的构象稳定性可以更好地理解 AD 中 tau 聚集的复杂性质以及渗透剂的保护性和/或离液剂性质。