Myricetin ameliorates cognitive impairment in 3×Tg Alzheimer's disease mice by regulating oxidative stress and tau hyperphosphorylation

Background: Alzheimer's disease is characterized by abnormal β-amyloid (Aβ) plaque accumulation, tau hyperphosphorylation, reactive oxidative stress, mitochondrial dysfunction and synaptic loss. Myricetin, a dietary flavonoid, has been shown to exert neuroprotective effects in vitro and in vivo. Here, we aimed to elucidate the mechanism and pathways involved in the protective effect of myricetin.

Methods: The effect of myricetin was assessed on Aβ₄₂ oligomer-treated neuronal SH-SY5Y cells and in 3×Tg mice. Behavioral tests were performed to assess the cognitive effects of myricetin (14 days, ip) in 3×Tg mice. The levels of beta-amyloid precursor protein (APP), synaptic and mitochondrial proteins, glycogen synthase kinase3β (GSK3β) and extracellular regulated kinase (ERK) 2 were assessed via Western blotting. Flow cytometry assays, immunofluorescence staining, and transmission electron microscopy were used to assess mitochondrial dysfunction and reactive oxidative stress.

Results: We found that, compared with control treatment, myricetin treatment improved spatial cognition and learning and memory in 3×Tg mice. Myricetin ameliorated tau phosphorylation and the reduction in pre- and postsynaptic proteins in Aβ₄₂ oligomer-treated neuronal SH-SY5Y cells and in 3×Tg mice. In addition, myricetin reduced Reactive Oxygen Species generation, lipid peroxidation, and DNA oxidation, and rescued mitochondrial dysfunction via the associated GSK3β and ERK 2 signalling pathways.

Conclusions: This study provides new insight into the neuroprotective mechanism of myricetin in vitro in Cell Culture and in vivo in a mouse model of Alzheimer's disease.

Alzheimer’s disease; Myricetin; Oxidative stress; Synaptic impairment; Tau.