Neuroprotective effects of donepezil against A beta 42-induced neuronal toxicity are mediated through not only enhancing PP2A activity but also regulating GSK-3 beta and nAChRs activity

作者：Noh Min Young; Koh Seong H; Kim Sung Min; Maurice Tangui; Ku Sae Kwang; Kim Seung H^*

来源：Journal of Neurochemistry, 2013, 127(4): 562-574.

DOI：10.1111/jnc.12319

• amyloid-beta
• donepezil
• GSK-3
• nAChRs
• neuroprotection
• PP2A

The main purpose of this study was to evaluate whether donepezil, acetylcholinesterase inhibitor, shown to play a protective role through inhibiting glycogen synthesis kinase-3 (GSK-3) activity, could also exert neuroprotective effects by stimulating protein phosphatase 2A (PP2A) activity in the amyloid-beta (A)42-induced neuronal toxicity model of Alzheimer%26apos;s disease. In A42-induced toxic conditions, each PP2A and GSK-3 activity measured at different times showed time-dependent reverse pattern toward the direction of accelerating neuronal deaths with the passage of time. In addition, donepezil pre-treatment showed dose-dependent stepwise increase of neuronal viability and stimulation of PP2A activity. However, such effects on them were significantly reduced through the depletion of PP2A activity with either okadaic acid or PP2Ac siRNA. In spite of blocked PP2A activity in this A42 insult, however, donepezil pretreatment showed additional significant recovering effect on neuronal viability when compared to the value without donepezil. Moreover, donepezil partially recovered its dephosphorylating effect on hyperphosphorylated tau induced by A42. This observation led us to assume that additional mechanisms of donepezil, including its inhibitory effect on GSK-3 activity and/or the activation role of nicotinic acetylcholine receptors (nAChRs), might be involved. Taken together, our results suggest that the neuroprotective effects of donepezil against A42-induced neurotoxicity are mediated through activation of PP2A, but its additional mechanisms including regulation of GSK-3 and nAChRs activity would partially contribute to its effects.

• 出版日期2013-11