l-3-n-Butylphthalide regulates amyloid precursor protein processing by PKC and MAPK pathways in SK-N-SH cells over-expressing wild type human APP695

Amyloid precursor protein (APP) is cleaved by α-secretase, within the amyloid-β (Aβ) sequence, resulting in the release of a secreted fragment (αAPPs) and precluding Aβ production. We investigated the effects of a promising anti-AD new drug, l-3-n-butylphthalide (L-NBP), on APP processing and Aβ generation in neuroblastoma SK-N-SH cells overexpressing wild-type human APP695. L-NBP significantly increased αAPPs release, and reduced Aβ generation. The steady-state full-length APP levels were unaffected by L-NBP. It suggested that L-NBP regulated APP processing towards to the non-amyloidogenic α-secretase pathway. Protein kinase C (PKC) and mitogen activated protein (MAP) kinase might be involved in L-NBP-induced αAPPs secretion. L-NBP significantly increased PKCα and ɛ activations, lowered PKCγ activation and increased the phosphorylation of p44/p42 MAPK. Furthermore, PKC and MAPK inhibitors partially reduced L-NBP-induced αAPPs secretion. The results suggested alternative pharmacological mechanisms of L-NBP regarding the treatment of Alzheimer's disease (AD).

Research highlights▶ L-NBP regulated APP processing towards to non-amyloidogenic α-secretase pathway. ▶ PKC isoforms activations may be involved in L-NBP-mediated αAPPs release. ▶ MAP kinase signaling pathway may be involved in L-NBP-regulated αAPPs release.