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).
Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China.
Ying
Y
Peng
Yanli
Y
Hu
Shaofeng
S
Xu
Nan
N
Feng
Ling
L
Wang
Xiaoliang
X
Wang
D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D001572:Benzofurans / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004365:Drugs, Chinese Herbal / Q000302:isolation & purification / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D010446:Peptide Fragments / Q000096:biosynthesis*; D011493:Protein Kinase C / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D012639:Seeds
D016564:Amyloid beta-Protein Precursor; D001572:Benzofurans; D004365:Drugs, Chinese Herbal; D010446:Peptide Fragments; C093597:amyloid beta-protein precursor 695 (18-38); C027125:3-n-butylphthalide; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases