Loss of age-accumulatedcrh-1circRNAs ameliorate amyloid β-induced toxicity in aC. elegansmodel 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), characterized by the accumulation of amyloid-beta (Aβ) proteins. In C. elegans , many circRNAs were previously found to accumulate during aging, with loss of age-accumulated circRNAs derived from the CREB gene (circ- crh-1 ) to increase mean lifespan. Here, we used C. elegans to study the effects of age-accumulated circRNAs on the age-related onset of Aβ-toxicity. We found that circ- crh-1 mutations delayed Aβ-induced muscle paralysis and lifespan phenotypes in a transgenic C. elegans strain expressing a full-length human Aβ-peptide (Aβ 1-42 ) selectively in muscle cells (GMC101). The delayed Aβ phenotypic defects were associated with inhibiting the deposition of Aβ aggregates, and thus, genetic removal of circ- crh-1 provides protection against Aβ-induced toxicity. Consistent with a detrimental role for age-accumulated circRNAs in AD, circ- crh-1 expression level is elevated after induction of Aβ during aging, whereas linear crh-1 mRNA expression remains unchanged. Finally, we show that a circ- crh-1 upregulated collagen gene, col-49 , promotes Aβ-induced paralysis. 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 C. elegans for studying circRNAs in AD and its relationship to aging.