Protective effects of a small molecule inhibitor ligand against hyperphosphorylated tau-induced mitochondrial and synaptic toxicities in Alzheimer disease.
Protective effects of a small molecule inhibitor ligand against hyperphosphorylated tau-induced mitochondrial and synaptic toxicities in Alzheimer disease.
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小分子抑制剂配体对阿尔茨海默病中过度磷酸化 tau 诱导的线粒体和突触毒性的保护作用。
DOI：
10.1093/hmg/ddab244
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发表时间：
2021
影响因子：
3.5
通讯作者：
Reddy,PHemachandra
中科院分区：
文献类型：
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作者：
Pradeepkiran,JangampalliAdi;Munikumar,Manne;Reddy,ArubalaP;Reddy,PHemachandra
我们研究的目的是了解磷酸化tau（p-tau）小分子配体在阿尔茨海默病（AD）进展中的保护作用。许多报告显示，磷酸化tau蛋白是AD神经元中成对螺旋丝（PHF）和神经纤维缠结（NFT）形成的重要贡献者。在AD中，糖原合成酶激酶-3 β（GSK 3 β）、细胞周期蛋白依赖性激酶-5和双特异性酪氨酸磷酸化调节激酶1A（DYRK 1A）是负责tau蛋白过度磷酸化的三种重要激酶。目前，没有药物和/或小分子降低AD中磷酸化tau的毒性。在本研究中，我们合理地选择并验证了在SER 23（Ser 285）和TYR 44（Tyr 310）处与磷酸化tau结合的小分子配体。我们还评估了分子动力学，并验证了三个最佳配体的分子对接位点。基于最佳对接评分-8.09、-7.9和-7.8 kcal/mol，我们发现配体1与磷酸化tau的关键过度磷酸化残基结合，这些残基抑制异常PHF-tau、DYRK 1A和GKS 3 β，从而降低AD中磷酸化tau水平。使用生化，分子，免疫印迹，免疫荧光和透射电镜分析，我们研究了配体1抑制以及永生化的原代海马神经元（HT 22）细胞的线粒体和突触保护作用。我们发现NAT 10 -262501（配体1）和磷酸化tau在关键磷酸化位点之间的相互作用，这些基于配体的抑制降低了PHF-tau、DYRK 1A和GSK 3 β水平。我们还发现，在配体1处理的突变体tau HT 22细胞中，线粒体生物发生、线粒体融合和突触活动增加，线粒体分裂减少。基于这些结果，我们谨慎地得出结论，磷酸化的tau NAT 10 -262501（配体1）减少了AD中基于tau的GKS 3 β和CDK 5激酶调节的过度磷酸化，并有助于维持神经元结构、线粒体动力学和生物发生，具有可能的AD治疗药物靶标。
The purpose of our study is to understand the protective effects of small molecule ligands for phosphorylated tau (p-tau) in Alzheimer’s disease (AD) progression. Many reports show evidence that phosphorylated tau is reported to be an important contributor to the formation of paired helical filaments (PHFs) and neurofibrillary tangles (NFTs) in AD neurons. In AD, glycogen synthase kinase-3 beta (GSK3β), cyclin-dependent kinase-5 and dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), are the three important kinases responsible for tau hyperphosphorylation. Currently, there are no drugs and/or small molecules that reduce the toxicity of phosphorylated tau in AD. In the present study, we rationally selected and validated small molecule ligands that bind to the phosphorylated tau at SER23 (Ser 285) and TYR44 (Tyr310). We also assessed the molecular dynamics and validated molecular docking sites for the three best ligands. Based on the best docking scores −8.09, −7.9 and −7.8 kcal/mol, we found that ligand 1 binds to key hyperphosphorylation residues of phosphorylated tau that inhibit abnormal PHF-tau, DYRK1A and GKS3β that reduce phosphorylated tau levels in AD. Using biochemical, molecular, immunoblotting, immunofluorescence and transmission electron microscopy analyses, we studied the ligand 1 inhibition as well as mitochondrial and synaptic protective effects in immortalized primary hippocampal neuronal (HT22) cells. We found interactions between NAT10-262501 (ligand 1) and phosphorylated tau at key phosphorylation sites and these ligand-based inhibitions decreased PHF-tau, DYRK1A and GSK3β levels. We also found increased mitochondrial biogenesis, mitochondrial fusion and synaptic activities and reduced mitochondrial fission in ligand 1-treated mutant tau HT22 cells. Based on these results, we cautiously conclude that phosphorylated tau NAT10-262501 (ligand 1) reduces hyperphosphorylation of tau based GKS3β and CDK5 kinase regulation in AD, and aids in the maintenance of neuronal structure, mitochondrial dynamics and biogenesis with a possible therapeutic drug target for AD.