Donepezil prevents olfactory dysfunction and α-synuclein aggregation in the olfactory bulb by enhancing autophagy in...

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 subventricular 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-α-synuclein (Ser129), α-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-α-synuclein (Ser129), and α-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 α-synuclein aggregation via the AMPK/mTOC1 pathway.