Ye_2015_Neuropharmacol_95_29

The main purpose of the present study is to investigate the influence of donepezil, a well-known acetylcholinesterase (AChE) inhibitor, on amyloid-beta (Abeta)-associated mitochondrial dysfunction, in order to gain a better understanding of the neuroprotective effects of this clinically used anti-Alzheimer's disease (AD) drug. First, our study verifies the ameliorative effects of donepezil on behavioral deficits in both working memory and anxiety in APP/PS1 double transgenic mice, at a time point that AChE is not inhibited. Meanwhile, we demonstrate that donepezil enhances the resistance of brain mitochondria of APP/PS1 mice to the induction of mitochondrial permeability transition (MPT) by calcium ions. Moreover, the level of mitochondrial Abeta in the brain of donepezil-treated APP/PS1 transgenic mice is significantly lower than that of vehicle-treated APP/PS1 mice. Our in vitro study using isolated mitochondria from rat brains, which is expected as an AChE-free subcellular system, further confirms the ameliorative effects of donepezil on oligomeric Abeta1-42 induced mitochondrial swelling and ATP reduction. In addition, donepezil treatment also significantly blocks the Abeta accumulation in the isolated mitochondria. Our study reported for the first time that the protective effects of donepezil against Abeta-associated mitochondrial dysfunction are closely associated with the reduction of Abeta accumulation in the mitochondria. Above observation led us to assume that, besides potent AChE inhibitory effect, other non-cholinergic mechanisms may be involved in the neuroprotective profiles of donepezil.