The circular RNA ci RS ‐7 promotes APP and BACE 1 degradation in an NF ‐κB‐dependent manner

The aberrant accumulation of β‐amyloid peptide (Aβ) in the brain is a key feature of Alzheimer's disease ( AD ), and enhanced cleavage of β‐amyloid precursor protein ( APP ) by β‐site APP ‐cleaving enzyme 1 ( BACE 1) has a major causative role in AD . Despite their prominence in AD pathogenesis, the regulation of BACE 1 and APP is incompletely understood. In this study, we report that the circular RNA circular RNA sponge for miR‐7 (ciRS‐7) has an important role in regulating BACE 1 and APP protein levels. Previous studies have shown that ci RS ‐7, which is highly expressed in the human brain, is down‐regulated in the brain of people with AD but the relevance of this finding was not clear. We have found that ci RS ‐7 is not involved in the regulation of APP and BACE 1 gene expression, but instead reduces the protein levels of APP and BACE 1 by promoting their degradation via the proteasome and lysosome. Consequently, overexpression of ci RS ‐7 reduces the generation of Aβ, indicating a potential neuroprotective role of ci RS ‐7. Our data also suggest that ci RS ‐7 modulates APP and BACE 1 levels in a nuclear factor‐κB (NF‐κB)‐dependent manner: ci RS ‐7 expression inhibits translation of NF‐κB and induces its cytoplasmic localization, thus derepressing expression of UCHL 1, which promotes APP and BACE 1 degradation. Additionally, we demonstrated that APP reduces the level of ci RS ‐7, revealing a mutual regulation of ci RS ‐7 and APP . Taken together, our data provide a molecular mechanism implicating reduced ci RS ‐7 expression in AD , suggesting that ci RS ‐7 may represent a useful target in the development of therapeutic strategies for AD .