Donepezil improves vascular function in a mouse model of Alzheimer's disease

Cardiovascular complications in Alzheimer's disease (AD) patients can occur years to decades prior to the onset of clinical symptoms of the disease. Donepezil represents the most effective drug in the treatment of AD. However, the potential effect of donepezil on vascular function and structure remains largely unexplored. Here, we assessed the impact of donepezil on the vascular phenotype of an established model of accelerated senescence that develops spontaneously AD, the SAMP8 mouse. Three groups of animals were included: SAMR1 (control strain), SAMP8, and SAMP8 treated with donepezil. Treatment with donepezil was administered from the 4th to the 6th month of life. At 6 months, after cognitive tests by Morris Water Maze, animals were euthanized, and their mesenteric arteries were processed for functional experiments. Untreated SAMP8 developed cognitive impairment compared to SAMR1, while donepezil treatment significantly attenuated cognitive dysfunction. SAMP8 exhibited a higher media-to-lumen ratio than SAMR1 and donepezil-treated animals. Endothelial function was impaired in SAMP8 animals compared to SAMR1. The addition of vitamin C improved the vasodilatory response to acetylcholine in SAMP8. Treatment with donepezil improved endothelial function in SAMP8 animals and reduced the additional vasodilation induced by vitamin C. In conclusion, in the SAMP8 AD model, cognitive impairment is associated with endothelial dysfunction and vascular remodeling which could contribute to cardiovascular events in AD since the prodromal phases of the disease. Treatment with donepezil alleviates vascular dysfunction associated with AD through an increase in NO availability likely by counteracting inflammation and oxidative stress.