Journal
NEUROSCIENCE LETTERS
Volume 487, Issue 2, Pages 211-216Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2010.10.025
Keywords
L-3-n-Butylphthalide; Amyloid precursor protein; A beta; Protein kinase C; Mitogen-activated protein kinase
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Funding
- National Natural Sciences Foundation of China [30973511]
- Natural Science Foundation of Beijing [7093125]
- National Science and Technology Major Special Project on Major New Drug Innovation of China [2008ZX09401-004, 2009ZX09303-003]
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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.
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