| Circular RNA aptamers targeting neuroinflammation ameliorate Alzheimer disease phenotypes in mouse models |
| 論文作者 |
Feng, X; Jiang, BW; Zhai, SN; Liu, CX; Wu, H; Zhu, BQ; Wei, MY; Wei, J; Yang, L; Chen, LL |
| 期刊/會(huì)議名稱 |
NATURE BIOTECHNOLOGY |
| 論文年度 |
2025 |
| 論文類別 |
|
| 摘要 |
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-beta 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. |
| 影響因子 |
41.7 |
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