Neurobiology Group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune, 411008, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
Cell Commun Signal. 2021 Feb 12;19(1):16. doi: 10.1186/s12964-021-00704-3.
Amyloid aggregate deposition is the key feature of Alzheimer's disease. The proteinaceous aggregates found in the afflicted brain are the intra-neuronal neurofibrillary tangles formed by the microtubule-associated protein Tau and extracellular deposits, senile plaques, of amyloid beta (Aβ) peptide proteolytically derived from the amyloid precursor protein. Accumulation of these aggregates has manifestations in the later stages of the disease, such as memory loss and cognitive inabilities originating from the neuronal dysfunction, neurodegeneration, and brain atrophy. Treatment of this disease at the late stages is difficult, and many clinical trials have failed. Hence, the goal is to find means capable of preventing the aggregation of these intrinsically disordered proteins by inhibiting the early stages of their pathological transformations. Polyphenols are known to be neuroprotective agents with the noticeable potential against many neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Prion diseases.
We analyzed the capability of Baicalein to inhibit aggregation of human Tau protein by a multifactorial analysis that included several biophysical and biochemical techniques.
The potency of Baicalein, a polyphenol from the Scutellaria baicalensis Georgi, against in vitro Tau aggregation and PHF dissolution has been screened and validated. ThS fluorescence assay revealed the potent inhibitory activity of Baicalein, whereas ANS revealed its mechanism of Tau inhibition viz. by oligomer capture and dissociation. In addition, Baicalein dissolved the preformed mature fibrils of Tau thereby possessing a dual target action. Tau oligomers formed by Baicalein were non-toxic to neuronal cells, highlighting its role as a potent molecule to be screened against AD.
In conclusion, Baicalein inhibits aggregation of hTau40 by enhancing the formation of SDS-stable oligomers and preventing fibril formation. Baicalein-induced oligomers do not affect the viability of the neuroblastoma cells. Therefore, Baicalein can be considered as a lead molecule against Tau pathology in AD. Video Abstract.
淀粉样蛋白聚集是阿尔茨海默病的关键特征。在受影响的大脑中发现的蛋白质聚集物是由微管相关蛋白 Tau 形成的神经元内神经原纤维缠结，以及淀粉样β（Aβ）肽的细胞外沉积物，即老年斑，该肽由淀粉样前体蛋白蛋白水解衍生而来。这些聚集物的积累在疾病的后期表现出来，例如记忆力丧失和认知能力下降，这些都是神经元功能障碍、神经退行性变和脑萎缩引起的。在疾病后期进行治疗很困难，许多临床试验都失败了。因此，目标是找到能够通过抑制其病理转化的早期阶段来防止这些无序蛋白聚集的方法。多酚已知是具有神经保护作用的物质，对许多神经退行性疾病具有显著的潜在作用，例如阿尔茨海默病、帕金森病和朊病毒病。
我们通过包括多种生物物理和生化技术的多因素分析来分析白杨素抑制人 Tau 蛋白聚集的能力。
筛选并验证了来自黄芩的多酚白杨素对 Tau 体外聚集和 PHF 溶解的效力。ThS 荧光测定法显示了白杨素的有效抑制活性，而 ANS 则揭示了其 Tau 抑制机制，即通过寡聚物捕获和解离。此外，白杨素溶解了 Tau 的预形成成熟纤维，从而具有双重靶向作用。白杨素形成的 Tau 寡聚物对神经元细胞没有毒性，突出了其作为针对 AD 进行筛选的有效分子的作用。
综上所述，白杨素通过增强 SDS 稳定寡聚物的形成和阻止纤维形成来抑制 hTau40 的聚集。白杨素诱导的寡聚物不会影响神经母细胞瘤细胞的活力。因此，白杨素可以被认为是 AD 中 Tau 病理的潜在药物。
