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.