circAβ RNA drives the formation and deposition of β-amyloid plaques in the sporadic Alzheimer’s disease

Abstract

Abstractβ-amyloid peptides (Aβ) play key causal role in Alzheimer’s disease (AD). However, the mechanisms of Aβ biogenesis in sporadic AD are still largely unknown. Moreover, current AD mouse models which overexpress mutated human APP and presenilin proteins can only mimic limited characteristics of familial AD. We recently discovered an alternative Aβ production pathway from Aβ175, an Aβ peptide containing polypeptide translated from circular circAβ-a RNA generated via backsplicing of the APP gene transcript. Here, wildtype human circAβ-a RNA was overexpressed in wildtype mouse frontal cortex. Results showed that circAβ-a overexpression drove intracellular Aβ accumulation and extensive depositions of neuronal Aβ plaques in mouse brain in vivo. This recapitulates the critical Aβ hallmarks of sporadic AD and represents a sporadic AD mouse model. In summary, the causal relationship between circAβ RNA overexpression and AD pathology was demonstrated. This novel AD mouse model will accelerate disease-modifying drug development of this detrimental neurodegenerative disease.