Bibliographic
Donepezil, an acetylcholinesterase inhibitor, is an approved drug for the treatment of Alzheimer's disease (AD). Although extensive studies have demonstrated the symptomatic efficacy of donepezil treatment in patients with AD, the effects of donepezil, if any, on the AD process are not known. In this study, the authors sought to determine whether long-term administration of donepezil would slow beta-amyloid plaque deposition or confer neuronal protection in the Tg2576 mouse model of AD. Administration of the 4 mg/kg dose of donepezil, as compared to vehicle and lower doses of donepezil, significantly reduced brain tissue soluble Aβ 1-40 and 1-42 peptides, Aβ plaque number, and burden at the study endpoint in Tg2576 mice. 4mg/kg of donepezil also significantly increased synaptic density in the molecular layer of the dentate gyrus in Tg2576 mice. However, a significant change of the synaptophysin-positive bouton in the hippocampus was not observed. These results suggest that a higher dose of donepezil may have a measurable impact on tissue level of Aβ protein, plaque deposition, and may prevent synapse loss in the Tg2576 mouse model of AD.