Nobiletin, a flavone from Citrus depressa, induces gene expression and increases the protein level and activity of neprilysin in SK-N-SH cells.

Neprilysin (NEP) is one of the candidate amyloid ß protein (Aß) degrading enzymes affecting brain Aß clearance. This enzyme declines in the brain with age, which leads to the increased Aß deposition in Alzheimer's disease (AD). Pharmacological activation of NEP during the aging process, therefore, represents a potential strategy to prevent the development of AD. To examine the influence of nobiletin on neprilysin activity, we measured cellular NEP activity in SK-N-SH cells. Moreover, NEP expression was examined by using reverse transcription - polymerase chain reaction and Western blotting. Measurement of cellular NEP activity showed that nobiletin stimulated this in a dose- and time-dependent manner in SK-N-SH cells. Moreover, nobiletin increased the expression of NEP mRNA, and then the levels of NEP protein, also in a dose- and time-dependent manner. Our findings showed that nobiletin promoted NEP gene and protein expression, resulting in enhancement of cellular NEP activity in SK-N-SH cells. This compound could be a novel Aß-degrading compound for use in the development of disease-modifying drugs to prevent and (or) cure AD.