Abstract

Here, we delineated the remarkably elevated neuroinflammation accompanied by progressive activation of double-stranded RNA (dsRNA)-activated Protein Kinase R (PKR) and PKR-related dsRNA pathways in hippocampus of 5xFAD mice upon Alzheimers disease (AD) progression. AAV-delivery of circular RNAs possessing short-imperfect duplex regions (ds-cRNAs) to neurons and microglia effectively dampened excessive PKR activity with little toxicity, accompanying with reduced neuroinflammation and amyloid-beta (A{beta}) plaques, resulting in neuroprotection and enhanced capability of spatial learning and memory in AD mouse models. These findings suggest a therapeutic potential of ds-cRNA aptamers as PKR inhibitors in AD therapy.