Abstract
Circular RNAs are universally expressed and evolutionarily conserved; however, the functions of most circRNAs are still unknown. Previous studies have shown that circRNAs are enriched in neurons and accumulate during brain ageing, indicating possible roles in ageing-associated neurodegenerative disorders. Alzheimer’s disease (AD) is the most common detrimental dementia, closely linked with advancing age. Amyloid-β (Aβ) peptide accumulation due to APP proteolytic processing is long believed to be the key step in AD neuropathology. Mutations in factors involved in Aβ peptide biogenesis have been shown to contribute to the mechanism of familial AD (FAD). However, this accounts for less than 1-5% of total AD patients, and mechanisms for the most common type of sporadic AD (SAD), remain largely unknown. Here, I demonstrate that a circRNA is expressed from the wild-type APP gene in human brain, encompassing the Aβ peptide sequence. Using my previously established circRNA expression strategy, I found Aβ circRNA-encoded expression of an Aβ related peptide, called Aβ circRNA-derived peptide, which up-regulates GSK3β levels and tau phosphorylation, both hallmarks of AD progression. Thus, Aβ circRNA and its translated peptide may not only play a causative role in AD, but represent promising therapeutic targets in AD diagnosis and treatment.
