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 alpha-secretase, within the amyloid-beta (A beta) sequence, resulting in the release of a secreted fragment (alpha APPs) and precluding A beta production. We investigated the effects of a promising anti-AD new drug, L-3-n-butylphthalide (L-NBP), on APP processing and A beta generation in neuroblastoma SK-N-SH cells overexpressing wild-type human APP695. L-NBP significantly increased aAPPs release, and reduced A beta 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 alpha-secretase pathway. Protein kinase C (PKC) and mitogen activated protein (MAP) kinase might be involved in L-NBP-induced alpha APPs secretion. L-NBP significantly increased PKC alpha and epsilon activations, lowered PKC gamma activation and increased the phosphorylation of p44/p42 MAPK. Furthermore, PKC and MAPK inhibitors partially reduced L-NBP-induced alpha APPs secretion. The results suggested alternative pharmacological mechanisms of L-NBP regarding the treatment of Alzheimer's disease (AD). (C) 2010 Elsevier Ireland Ltd. All rights reserved.