Donepezil ameliorates Aβ pathology but not tau pathology in 5xFAD mice

Abstract

The cholinesterase inhibitor donepezil is used to improve Aβ 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 Aβ 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 Aβ plaque number in the cortex and hippocampal DG region. In addition, donepezil treatment (1 mg/kg, i.p.) reduced Aβ-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 Aβ pathology but not tau pathology in 5xFAD mice.

RETRACTED ARTICLE: Polyphenols from Conyza dioscoridis (L.) ameliorate Alzheimer’s disease- like alterations through multi-targeting activities in two animal models

“…Our result showed a significantly lower Aβ deposition as with DON and reduced p-tau more than with DON. The effect of DON used as a reference drug documents the effect of PCDE on Aβ and tau protein [64][65][66]. Polyphenols decrease amyloid, tau, α-syn, and synphilin-1 deposits, by inhibition of their formation or by disaggregation of them [67][68][69].…”

The function of astrocytes and their role in neurological diseases

“…Previous studies have shown that retinal ganglion cells (RGCs) undergo a significant increase in synapse number in astrocyte conditioned medium (ACM) (Meyer-Franke et al, 1995). When thrombospondin (TSP) was added to RGC cultures, it was found that synapse number increased to a similar level as in ACM cultures, while the removal of TSP resulted in the loss of most synaptic activity in ACM (Christopherson et al, 2005). It indicates that astrocytes may affect the formation of RGC synapses through TSP.…”

“…It indicates that astrocytes may affect the formation of RGC synapses through TSP. In addition, the TSP content tends to increase when the adult mice suffer from central system damage caused by stroke ischemia, and the lack of TSPs hinders the synaptic recovery after stroke (Christopherson et al, 2005;Eroglu et al, 2009;Liauw et al, 2008). It indicates that astrocytes may affect the formation of RGC synapses through TSP.…”

“…Acetylcholinesterase inhibitors, such as Donepezil, reduce neuroinflammatory responses through Akt/MAPK signalling, NLRP3 inflammasome regulation and phosphorylation of transcription factors (NK‐κB/STAT3) (Kim et al, 2021). In 5xFAD mice, Donepezil significantly reduces Aβ‐induced astrocyte activation but does not inhibit tau pathology (Choi et al, 2022; Kim et al, 2021). GJ‐4 is a natural extract from the TCM herb Gardenia jasminoides .…”

The past and present of therapeutic strategy for Alzheimer’s diseases: potential for stem cell therapy

“…The FDA has also approved three AChE inhibitors, donepezil (in 1996), rivastigmine (in 1998), and galantamine (in 2001), in addition to the N-methyl-Daspartate receptor antagonist, memantine (in 2003), which acts on glutamatergic antidepressants [73]. Donepezil and rivastigmine have been reported to affect the formation of SPs, but not the hyperphosphorylation of tau, in AD model mice [74].…”