A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer's mouse model via an HSF1-mediated mechanism.
A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer's mouse model via an HSF1-mediated mechanism.
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DOI：
10.1038/mp.2016.104
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发表时间：
2017-07
影响因子：
11
通讯作者：
Liao FF
中科院分区：
文献类型：
--
作者：
Wang B;Liu Y;Huang L;Chen J;Li JJ;Wang R;Kim E;Chen Y;Justicia C;Sakata K;Chen H;Planas A;Ostrom RS;Li W;Yang G;McDonald MP;Chen R;Heck DH;Liao FF
目前正在研究通过药物Hsp90抑制剂诱导神经保护性热休克蛋白作为神经退行性疾病的潜在治疗方法。治疗使用Hsp90抑制剂的两个主要障碍是全身毒性和有限的中枢神经系统通透性。我们在这里证明，使用专有的Hsp90抑制剂化合物（OS47720）进行慢性治疗不仅可以引起热休克样反应，而且还可以在有症状的Tg2576小鼠（阿尔茨海默病（AD）模型）中提供突触保护，没有明显的全身毒性。尽管OS47720在小鼠脑中的半衰期较短，但单次腹腔注射可诱导热休克因子HSF1的快速且持久（bbb30 d）的核激活。机制研究表明，OS47720的治疗作用依赖于HSF1的激活和随后hsf -1介导的突触基因转录事件。综上所述，这项工作揭示了HSF1在突触功能和记忆中的新作用，这可能是通过突触转录组的调节发生的。
Induction of neuroprotective heat-shock proteins via pharmacological Hsp90 inhibitors is currently being investigated as a potential treatment for neurodegenerative diseases. Two major hurdles for therapeutic use of Hsp90 inhibitors are systemic toxicity and limited CNS permeability. We demonstrate here that chronic treatment with a proprietary Hsp90 inhibitor compound (OS47720) not only elicits a heat shock-like response, but also offers synaptic protection in symptomatic Tg2576 mice, a model of Alzheimer’s disease (AD), without noticeable systemic toxicity. Despite a short half-life of OS47720 in mouse brain, a single intraperitoneal injection induces rapid and long-lasting (> 3 d) nuclear activation of the heat shock factor, HSF1. Mechanistic study indicates that the remedial effects of OS47720 depend upon HSF1 activation and the subsequent HSF-1-mediated transcriptional events on synaptic genes. Taken together, this work reveals a novel role of HSF1 in synaptic function and memory, which likely occurs through modulation of the synaptic transcriptome.