Circular RNA Encoded Amyloid Beta peptides-A Novel Putative Player in Alzheimer's Disease

Alzheimer's disease (AD) is an age-related detrimental dementia. Amyloid beta peptides (A beta) play a crucial role in the pathology of AD. In familial AD, A beta are generated from the full-length amyloid beta precursor protein (APP) via dysregulated proteolytic processing; however, in the case of sporadic AD, the mechanism of A beta biogenesis remains elusive. circRNAs are a class of transcripts preferentially expressed in brain. We identified a circRNA harboring the A beta-coding region of the APP gene termed circA beta-a. This circular RNA was detected in the brains of AD patients and non-dementia controls. With the aid of our recently established approach for analysis of circRNA functions, we demonstrated that circA beta-a is efficiently translated into a novel A beta-containing A beta 175 polypeptide (19.2 KDa) in both cultured cells and human brain. Furthermore, A beta 175 was shown to be processed into A beta peptides-a hallmark of AD. In summary, our analysis revealed an alternative pathway of A beta biogenesis. Consequently, circA beta-a and its corresponding translation product could potentially represent novel therapeutic targets for AD treatment. Importantly, our data point to yet another evolutionary route for potentially increasing proteome complexity by generating additional polypeptide variants using back-splicing of primary transcripts that yield circular RNA templates.