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The involvement of mitogen‐activated protein (MAP) kinase in the regulation of amyloid precursor protein processing by novel cholinesterase inhibitors derived from rasagiline
Author(s) -
YogevFalach Merav,
Amit Tamar,
BarAm Orit,
Weinstock Marta,
Youdim Moussa B.H.
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0198fje
Subject(s) - protein kinase a , chemistry , protein kinase c , rasagiline , map kinase kinase kinase , biochemistry , kinase , mitogen activated protein kinase , amyloid precursor protein , signal transduction , mitogen activated protein kinase kinase , pharmacology , biology , alzheimer's disease , medicine , parkinson's disease , disease
Two novel neuroprotective cholinesterase (ChE) inhibitors, TV3326, (N‐propargyl‐(3R) aminoindan‐5‐yl)‐ethyl methyl carbamate, and TV3279, (N‐propargyl‐(3S) aminoindan‐5‐yl)ethyl methyl carbamate, were derived from rasagiline for the treatment of Alzheimer's disease (AD). TV3326 also inhibits monoamine oxidase (MAO)‐A and ‐B, whereas its S‐isomer, TV3279, lacks MAO inhibitory activity. The action of these drugs in the regulation of amyloid precursor protein (APP) processing, using rat PC12 and human SH‐SY5Y neuroblastoma cells, was examined. Both isomers stimulated the release of the non‐amyloidogenic α‐secretase form of soluble APP (sAPPα) from these cell lines. The increases in sAPPα, induced by TV3326 and TV3279, were dose‐dependent (0.1–100 μM) and blocked by the hydroxamic acid‐based metalloprotease inhibitor, Ro31–9790, suggesting mediation via α‐secretase activity. Using several signal transduction inhibitors, we identified the involvement of protein kinase C (PKC), mitogen‐activated protein (MAP) kinase, and tyrosine kinase‐dependent pathways in the enhancement of sAPPα release by TV3326 and TV3279. In addition, both drugs directly induced the phosphorylation of p44 and p42 MAP kinase, which was abolished by the specific inhibitors of MAP kinase activation, PD98059 and U0126. These data suggest a novel pharmacological mechanism whereby these ChE inhibitors regulate the secretory processes of APP via activation of the MAP kinase pathway.