Abstract
CircRNAs enrich in neurons and accumulate during brain ageing, indicating possible roles in age-associated neurodegenerative diseases.
Alzheimer’s disease (AD) is the most common detrimental dementia. Studies show amyloid-β (Aβ) peptide plays key role in AD. Aβ could accumulate from the full-length APP proteolytic processing, especially in familial AD, but the mechanism of Aβ biogenesis in sporadic AD remains largely unknown.
Here, we demonstrate that a couple of circRNAs are expressed from APP gene, encompassing the Aβ sequence. They are named as Aβ circRNAs. Using circRNA expression strategy based on intron mediated enhancement (IME), we found Aβ circRNA encoded Aβ related peptide. Importantly, this peptide is further processed to produce Aβ, thus representing an alternative mechanism of Aβ biogenesis.
Furthermore, Aβ circRNA up-regulates GSK3β levels and tau phosphorylation, both hallmarks of AD. Thus, Aβ circRNA and translated peptides may not only play a causative role in AD but represent promising therapeutic targets in the AD medicine.