靶向神经炎症的环状RNA适体改善小鼠模型中的阿尔茨海默病表型，这一成果由中国科学院大学陈玲玲研究小组经过不懈努力而取得。2025年3月31日出版的《自然—生物技术》发表了这项成果。

研究人员在两个含有短双链区域的AD主题环状RNA（ds-cRNAs）的小鼠模型中靶向PKR，其结构与研究人员之前在牛皮癣模型中靶向PKR的主题相似。该课题组研究人员发现，通过腺相关病毒（AAV）在海马内向神经元和小胶质细胞注射ds-cRNAs，有效地抑制了PKR的过度活性，毒性最小，并伴有神经炎症和淀粉样β斑块的减少。该课题组研究人员还通过静脉注射AAV-PHP.eB将ds-cRNAs传递到整个大脑。AAV-PHP.eB穿过血脑屏障，在AD主题模型中产生神经保护和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。

据介绍，阿尔茨海默病（AD）的治疗可能受益于优化的方法来抑制神经炎症。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模型中有疗效，但其效用受到不良副作用的影响。

附：英文原文

Title: Circular RNA aptamers targeting neuroinflammation ameliorate Alzheimer disease phenotypes in mouse models

Author: 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

Issue&Volume: 2025-03-31

Abstract: 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 6months after a single administration.

DOI: 10.1038/s41587-025-02624-w

Source: https://www.nature.com/articles/s41587-025-02624-w