阿尔茨海默病中的Tau低聚物:渗透细胞对脑源性Tau低聚物扩增的调节作用。

IF 3.9 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Sharif Arar*, Md. Anzarul Haque, Anas Kayed, Sheeza Khan, Nemil Bhatt, Yingxin Zhao and Rakez Kayed*, 
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引用次数: 0

摘要

Tau蛋白与微管结合,在微管的组装和空间组织中起着关键作用。在病理条件下,tau蛋白从微管中分离出来,并倾向于自聚集成可溶性tau低聚物(TauO)、成对的螺旋细丝和神经原纤维缠结。最近的研究表明,TauO是一种有毒的物种,负责tauopathies的播种、繁殖和发展。可以调节TauO形成过程的策略可以帮助减少TauO的毒性并阻止疾病的进展。渗透物是天然存在的小分子量有机化合物,它对蛋白质的适当折叠至关重要,从而影响蛋白质的稳定性和溶解度。因此,渗透物可以作为调节TauO的良好候选者。渗透细胞穿过血脑屏障,充当伴侣,防止蛋白质错误折叠和聚集。在这里,我们研究了不同的脑渗透液对扩增脑源性tau寡聚物(aBDTO)的影响。我们的研究表明,脑渗透细胞对aBDTO的调节是不同的。渗透物山梨醇和甘油磷酸胆碱(GPC)通过将前体tau寡聚物分解成具有不同构象的较小组装物,显示出减少大聚集体形成和积累的潜力。这可能是由于这些渗透物调节聚集的tau的构象,这可能导致其播种潜力的降低。然而,氧化三甲胺(TMAO)已被发现能显著地阻止和清除aBDTO的形成。瓜氨酸不如氧化三甲胺有效,可能影响更多二聚体物种。这些渗透细胞可以成为治疗阿尔茨海默病不可或缺的工具和混合治疗机制的一部分,此外还可以更好地了解tau寡聚化和种子能力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Tau Oligomers in Alzheimer’s Disease: Modulation Effect of Osmolytes on Amplified Brain-Derived Tau Oligomers

Tau is bound to microtubules and plays a key role in their assembly and spatial organization. Under pathological conditions, tau detaches from the microtubules and develops a propensity to self-aggregate into soluble tau oligomers (TauO), paired helical filaments, and neurofibrillary tangles. Recent studies have revealed that TauO is the toxic species responsible for seeding, propagation, and development of tauopathies. Strategies that can modulate the process of TauO formation can help reduce the toxicity of TauO and stop the progression of the disease. Osmolytes are naturally occurring small-molecular-weight organic compounds, which crucially assist in the proper protein folding and thus impact the stability and solubility of proteins. Therefore, osmolytes can serve as good candidates for modulating TauO. Osmolytes cross the blood-brain barrier and act as chaperons to prevent the proteins from misfolding and aggregation. Here, we investigated the effect of different brain osmolytes against the amplified brain-derived tau oligomer (aBDTO). Our investigations have revealed that the brain osmolytes modulate the aBDTO differentially. The osmolytes sorbitol and glycerophosphocholine (GPC) displayed the potential to reduce the formation and accumulation of large aggregates by disaggregating the precursor tau oligomers into smaller assemblies with varying conformations. This may result from these osmolytes modulating the conformation of aggregated tau, which could lead to reduction in its seeding potential. However, trimethyl amine oxide (TMAO) has been found to prevent and clear out the formation of aBDTO significantly. Citrulline is less effective than TMAO and possibly affects more dimeric species. These osmolytes can become an indispensable tool for the management of Alzheimer’s disease and part of hybrid therapeutic mechanisms, in addition to providing better understanding of tau oligomerization and seeding ability.

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来源期刊
ACS Chemical Neuroscience
ACS Chemical Neuroscience BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
9.20
自引率
4.00%
发文量
323
审稿时长
1 months
期刊介绍: ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following: Neurotransmitters and receptors Neuropharmaceuticals and therapeutics Neural development—Plasticity, and degeneration Chemical, physical, and computational methods in neuroscience Neuronal diseases—basis, detection, and treatment Mechanism of aging, learning, memory and behavior Pain and sensory processing Neurotoxins Neuroscience-inspired bioengineering Development of methods in chemical neurobiology Neuroimaging agents and technologies Animal models for central nervous system diseases Behavioral research
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