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P4–267: ADAM10 activation is required for green tea EGCG–induced alpha–secretase cleavage of amyloid precursor protein
Author(s) -
Tan Jun,
Obregon Demian,
Rezai-Zadeh Kavon,
Bai Yun,
Sun Nan,
Hou Huayan,
Zeng Jin,
Mori Takashi,
Arndash Gary,
Shytle Doug,
Town Terrence
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.2006
Subject(s) - adam10 , amyloid precursor protein , alpha secretase , amyloid precursor protein secretase , chemistry , metalloproteinase , presenilin , cleavage (geology) , p3 peptide , neuroprotection , peptide , biochemistry , protein precursor , disintegrin , microbiology and biotechnology , alzheimer's disease , enzyme , biology , pharmacology , medicine , paleontology , disease , fracture (geology)
Objective(s): We investigated, therefore, the effect of the nicotinic acetylcholine receptor (nAChR) stimulation on A -related neuronal death, using nicotine or acetylcholinesterase inhibitors (AChEIs) which could augment acetylcholine levels. Effects of nicotine or AChEIs on alphasecretase activities were also examined. Methods: Cultured rat cortical neurons were prepared. The number of neurons was evaluated by counting neurons stained with anti-MAP2 antibody. Neurotoxicity in each experiment was defined as a reduction in the survival rate. Akt phosphorylation was evaluated by immunoblot using anti-phosphorylated Akt antibodies. The levels of sAPPalpha, C83 or A were analyzed using immunoblot or ELISA. Results: Nicotine (10 M, 24 hr pretreatment) protected neurons against A and glutamate-induced neurotoxicity, which was blocked by an alpha7 nicotinic receptor antagonist (alpha-bungarotoxin), a phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002 and wortmannin), and a Src inhibitor (PP2). Levels of phosphorylated Akt, an effector of PI3K, and Bcl-2 were increased by nicotine. AChEIs, such as donepezil (10 M, 24 hr pre-treatment) and galantamine (10 M, 24 hr pre-treatment), also protected neurons against the toxicity. Akt phosphorylation was also induced by AChEIs, indicating the involvement of PI3K. We next examined the effect on the secretase activities. Nicotine or AChEI treatment significantly increased the C83 level. Furthermore, sAPPalpha released into the medium was also increased by the administration of nicotine (10 M, 24 hr), donepezil (10 M, 24 hr) or galantamine (10 M, 24 hr). On the contrary, the levels of A 42 and A 40 in culture medium were significantly decreased. Conclusions: Stimulation of the nAChR exerts neuroprotective effects, and shifts the amyloidogenic pathway of APP metabolism to the non-amyloidogenic one. These effects might play, at least in part, key roles on AD treatment.