Abstract
CircRNAs are ubiquitously expressed in brain and accumulated at higher levels within brain ageing, suggesting that they may play ageing-associated neurological roles.
Alzheimer’s disease (AD) is the most prevalent form of detrimental dementia (brain disorder). Today it is known that the amyloid-β (Aβ) peptide plays a key role in the development of AD. In particular, in case of familial AD, Aβ peptides are generated from full-length APP by dysregulated proteolytic processing. However, the actual mechanism of Aβ biogenesis in sporadic AD remains largely unknown.
Here we reported the identification of 17 circRNAs that are derived from the APP gene and encompass the Aβ coding region. In accordance, they are named Aβ circRNAs. In accordance, they are named Aβ circRNAs. Using a well-established circRNA expression strategy, which is based on intron mediated enhancement (IME), we discovered an Aβ-related peptide from Aβ circRNA translation. Importantly, this peptide is further processed to form Aβ and the generation of amyloid-β plaques in primary neuron culture, significantly recapitulating the key hallmark of AD pathology and representing an alternative mechanism of Aβ biogenesis.
Furthermore, Aβ circRNA up-regulates GSK3β levels and correspondingly causes tau phosphorylation, another hallmark of AD. Thus, Aβ circRNA and translated peptides may not only play a causative role in AD but might represent therapeutic targets for the development of AD treatment.