Donepezil ameliorates A beta pathology but not tau pathology in 5xFAD mice

Abstract

The cholinesterase inhibitor donepezil is used to improve A beta pathology and cognitive function in patients with Alzheimer's disease (AD). However, the impact of donepezil on tau pathology is unclear. Thus, we examined the effects of donepezil on A beta and tau pathology in 5xFAD mice (a model of AD) in this study. We found that intraperitoneal injection of donepezil (1 mg/kg, i.p.) exhibited significant reductions in A beta plaque number in the cortex and hippocampal DG region. In addition, donepezil treatment (1 mg/kg, i.p.) reduced A beta-mediated microglial and, to a lesser extent, astrocytic activation in 5xFAD mice. However, neither intraperitoneal/oral injection of donepezil nor oral injection of rivastigmine altered tau phosphorylation at Thr212/Ser214 (AT100), Thr396, and Thr231 in 5xFAD mice. Surprisingly, we observed that intraperitoneal/oral injection of donepezil treatment significantly increased tau phosphorylation at Thr212 in 5xFAD mice. Taken together, these data suggest that intraperitoneal injection of donepezil suppresses A beta pathology but not tau pathology in 5xFAD mice.