Abstract
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, we sought to determine whether long-term administration of donepezil would slow amyloid plaque deposition or confer neuronal protection in a mouse model of AD. We used quantitative light and electron microscopy to investigate the effects of long-term administration (from 3 to 9 months of age for 6 months of treatment) of donepezil (1, 2, 4 mg/kg, in drinking water) on tissue amyloid-beta (Abeta) protein, plaque deposition, synaptic protein (synaptophysin), and synapse density in the hippocampus of Tg2576 mice. Administration of the 4 mg/kg dose of donepezil, as compared to vehicle and lower doses of donepezil, significantly reduced brain tissue soluble Abeta(1-40) and Abeta(1-42), Abeta plaque number, and burden at the study end point in Tg2576 mice. The dose of 4 mg/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 Abeta protein and plaque deposition and may prevent synapse loss in the Tg2576 mouse model of AD.