The main purpose of this study was to evaluate whether
donepezil,
acetylcholinesterase inhibitor, shown to play a protective role through inhibiting
glycogen synthesis kinase-3β (GSK-3β) activity, could also exert
neuroprotective effects by stimulating
protein phosphatase 2A (PP2A) activity in the
amyloid-beta (Aβ)42-induced neuronal toxicity model of
Alzheimer's disease. In Aβ42-induced toxic conditions, each PP2A and GSK-3β 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 Aβ42 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 Aβ42. This observation led us to assume that additional mechanisms of
donepezil, including its inhibitory effect on GSK-3β 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 Aβ42-induced neurotoxicity are mediated through activation of PP2A, but its additional mechanisms including regulation of GSK-3β and nAChRs activity would partially contribute to its effects. We investigated neuroprotective mechanisms of
donepezil against Aβ42 toxicity:
Donepezil increased neuronal viability with reduced p-tau by enhancing PP2A activity. Despite of blocked PP2A activity,
donepezil showed additional recovering effect on neuronal viability, which findings led us to assume that additional mechanisms of
donepezil including its inhibitory effect on GSK-3β activity and activating role of nicotinic AChRs might be involved.