Donepezil prevents olfactory dysfunction and α-synuclein aggregation in the olfactory bulb by enhancing autophagy in zinc sulfate-treated mice

Alzheimer's disease is associated with marked olfactory dysfunction observed in the early stages. Clinical studies reported that acetylcholinesterase inhibitor donepezil (DNP) attenuated this deficit; however, the underlying mechanism remains unclear. Herein, we aimed to examine the effects and underlying mechanisms of DNP on olfactory deficits in zinc sulfate (ZnSO4) nasal-treated mice, which were used as a model of reversible olfactory impairment. We evaluated olfactory function using the buried food finding test and neurogenesis in the sub -ventricular zone (SVZ) using immunohistochemistry. Finally, we measured the expression of doublecortin (DCX), neuronal nuclear antigen (NeuN), olfactory marker protein, tyrosine hydroxylase (TH), tryptophan hydroxylase 2, glutamic acid decarboxylase 67, p-alpha-synuclein (Ser129), alpha-synuclein, p-AMPK, p-p70S6 kinase (p70S6K) (Thr389), LC3 II/I, and p-p62 in the olfactory bulb (OB) by western blotting. On day 7 after treatment, ZnSO4- treated mice exhibited prolonged time to find the buried food, cell proliferation enhancement in the SVZ, increased NeuN, p-alpha-synuclein (Ser129), and alpha-synuclein levels, and decreased DCX and TH levels in the OB; except for TH, these changes normalized on day 14 after treatment. Repeated administration of DNP prevented the ZnSO4-induced changes on day 7 after treatment. Moreover, DNP increased p-AMPK and LC3 II/I, and decreased p-p70S6K and p-p62 (Ser351) levels in the OB, suggesting that DNP enhances autophagy in the OB. These findings indicate that DNP may help prevent olfactory dysfunction by autophagy that reduces alpha-synuclein aggregation via the AMPK/mTOC1 pathway.

Automated summary

This study found that the acetylcholinesterase inhibitor donepezil (DNP) can prevent olfactory dysfunction and reduce alpha-synuclein aggregation through enhancing autophagy in a mouse model of reversible olfactory impairment. These findings have important implications for preventing olfactory dysfunction associated with Alzheimer's disease.