Feng Xin, Jiang Bo-Wen, Zhai Si-Nan, Liu Chu-Xiao, Wu Hao, Zhu Bang-Qi, Wei Meng-Yuan, Wei Jia, Yang Li, Chen Ling-Ling
Key Laboratory of RNA Innovation, Science and Engineering, New Cornerstone Science Laboratory, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Center for Molecular Medicine, Children's Hospital of Fudan University and Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Nat Biotechnol. 2025 Mar 31. doi: 10.1038/s41587-025-02624-w.
Alzheimer disease (AD) therapy may benefit from optimized approaches to inhibit neuroinflammation. Small-molecule inhibitors of the proinflammatory molecule double-stranded RNA (dsRNA)-activated protein kinase R (PKR) have efficacy in AD models but their utility is compromised by adverse side effects. Here, we target PKR in two mouse models of AD using circular RNAs containing short double-stranded regions (ds-cRNAs), which are structurally similar to what we used previously to target PKR in psoriasis models. We show that the intrahippocampal injection of ds-cRNAs to neurons and microglia by adeno-associated virus (AAV) effectively dampens excessive PKR activity with minimal toxicity, accompanied by reduced neuroinflammation and amyloid-β plaques. We also deliver ds-cRNAs to the whole brain through intravenous injection of AAV-PHP.eB, which crosses the blood-brain barrier, resulting in neuroprotection and enhanced capability of spatial learning and memory in AD mouse models. The delivery of ds-cRNAs at different progressive stages of AD alleviates disease phenotypes, with therapeutic effects sustained for at least 6 months after a single administration.
阿尔茨海默病（AD）治疗可能受益于抑制神经炎症的优化方法。促炎分子双链RNA（dsRNA）激活蛋白激酶R（PKR）的小分子抑制剂在AD模型中具有疗效，但它们的效用因不良副作用而受到影响。在这里，我们使用含有短双链区域的环状RNA（ds-cRNAs）在两种AD小鼠模型中靶向PKR，其结构与我们之前在银屑病模型中用于靶向PKR的结构相似。我们表明，通过腺相关病毒（AAV）将ds-cRNAs海马内注射到神经元和小胶质细胞中，能以最小的毒性有效抑制过度的PKR活性，同时减少神经炎症和淀粉样β斑块。我们还通过静脉注射能穿越血脑屏障的AAV-PHP.eB将ds-cRNAs递送至全脑，从而在AD小鼠模型中实现神经保护并增强空间学习和记忆能力。在AD的不同进展阶段递送ds-cRNAs可减轻疾病表型，单次给药后治疗效果可持续至少6个月。
