Donepezil attenuates Aβ-associated mitochondrial dysfunction and reduces mitochondrial Aβ accumulation in vivo and in vitro.
The main purpose of the present study is to investigate the influence of donepezil, a well-known acetylcholinesterase (AChE) inhibitor, on amyloid-β (Aβ)-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 Aβ 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 Aβ1-42 induced mitochondrial swelling and ATP reduction. In addition, donepezil treatment also significantly blocks the Aβ accumulation in the isolated mitochondria. Our study reported for the first time that the protective effects of donepezil against Aβ-associated mitochondrial dysfunction are closely associated with the reduction of Aβ 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.
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, People's Republic of China.
Chun Yan
CY
Ye
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, People's Republic of China.
Yun
Y
Lei
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, People's Republic of China.
Xi Can
XC
Tang
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, People's Republic of China. Electronic address: hzhang@simm.ac.cn.
Hai Yan
HY
Zhang
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D008297:Male; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley
C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D007189:Indans; D018696:Neuroprotective Agents; C508853:PSEN1 protein, human; D010880:Piperidines; D053764:Presenilin-1; D000077265:Donepezil
Alzheimer's disease; Amyloid-β; Donepezil; Mitochondrial dysfunction; Oligomer