Lycium barbarum extract improves brain and visual functions in mice models of Alzheimer's disease through activating WNT pathway

Abstract

Background: Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by visual deficits and cognitive impairment. However, current therapies have limited efficacy. Purpose: This study aims to investigate whether Lycium barbarum extract (LBE) can mitigate the decline in brain and visual function in mouse models of AD during the middle and late stages. Methods: The chemical constituents of LBE were identified using Liquid Chromatography-Mass Spectrometry. LBE was administered daily to 5xFAD mice for one month and to 3xTG mice for two months, via the intragastric route, until the middle and late stages of AD. Visual and brain functions were assessed through behavioral tests and electrophysiological recordings. The structure of the hippocampal region and retina was evaluated using immunostaining. RNA sequencing and western blotting were performed to explore potential mechanisms. Results: Sixteen compounds were identified in LBE, with lycibarbarspermidines and rutin being the major components. Functionally, LBE significantly improved memory and light responses of retinal ganglion cells in both 5xFAD and 3xTG mice. It also enhanced long-term potentiation in the hippocampus of 5xFAD mice and cortical visual function in 3xTG mice. Structurally, LBE reduced hippocampal Aβ deposits in 5xFAD mice and Tau phosphorylation in 3xTG mice. In the retinas of 3xTG mice, LBE increased ganglion cell survival and inhibited inflammation and oxidative stress. Mechanistically, LBE restored the expression of WNT5a/b and KRAS, and inhibited GSK3β activation in the retinas of 3xTG mice. Conclusion: Our findings suggest that LBE can alleviate visual and brain function deterioration in various AD mouse models, even at the middle or late stages, possibly through the activation of the WNT pathway leading to the inhibition of Tau phosphorylation. This study reveals a novel mechanism of LBE action and proposes a promising strategy for treating AD patients using natural plant extracts, even at advanced stages.