Circular RNA aptamers targeting neuroinflammation ameliorate Alzheimer disease phenotypes in mouse models
Feng X., Jiang BW., Zhai SN., Liu CX., Wu H., Zhu BQ., Wei MY., Wei J., Yang L., Chen LL.
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.