Loss of age-accumulated crh-1 circRNAs ameliorate amyloid β-induced toxicity in a C. elegans model for Alzheimer’s disease

Circular RNAs (circRNAs) are non-coding RNAs mostly derived from exons of protein-coding genes via a back-splicing process. The expression of hundreds of circRNAs accumulates during healthy aging and is associated with Alzheimer's disease (AD), which is characterized by the accumulation of amyloid-beta (Aβ) proteins. In <i>C. elegans</i>, many circRNAs were previously found to accumulate during aging, with loss of age-accumulated circRNAs derived from the CREB gene (circ-<i>crh-1</i>) to increase mean lifespan. Here, we used <i>C. elegans</i> to study the effects of age-accumulated circRNAs on the age-related onset of Aβ-toxicity. We found that circ-<i>crh-1</i> mutations delayed Aβ-induced muscle paralysis and lifespan phenotypes in a transgenic <i>C. elegans</i> strain expressing a full-length human Aβ-peptide (Aβ_1-42) selectively in muscle cells (GMC101). The delayed Aβ phenotypic defects were associated with the inhibition of Aβ aggregate deposition, and thus, genetic removal of circ-<i>crh-1</i> alleviated Aβ-induced toxicity. Consistent with a detrimental role for age-accumulated circRNAs in AD, the expression level of circ-<i>crh-1</i> expression is elevated after induction of Aβ during aging, whereas linear <i>crh-1</i> mRNA expression remains unchanged. Finally, we found that the delayed onset of Aβ-induced paralysis observed in circ-<i>crh-1</i> mutants is dependent on the <i>col-49</i> collagen gene. Taken together, our results show that the loss of an age-accumulated circRNA exerts a protective role on Aβ-induced toxicity, demonstrating the utility of <i>C. elegans</i> for studying circRNAs in AD and its relationship to aging.