Magnolol Ameliorates Behavioral Impairments and Neuropathology in a Transgenic Mouse Model of Alzheimer's Disease.

Yan-Fang Xian,Zhi-Xiu Lin,Siu-Po Ip,Yue Liu,Chang Qu,Qiu-Ju Yuan,Wen Yang

doi:10.1155/2020/5920476

Abstract

Alzheimer's disease (AD) is a common neurodegenerative disease characterized by progressive memory loss. Magnolol (MN), the main active ingredient of Magnolia officinalis, possesses anti-AD effects in several experimental models of AD. In this study, we aimed to explore whether MN could ameliorate the cognitive deficits in TgCRND8 transgenic mice and to elucidate its molecular mechanisms. Male TgCRND8 mice were orally administered with MN (20 and 40 mg/kg) daily for 4 consecutive months, followed by assessing the spatial learning and memory functions using the open-field, radial arm maze, and novel object recognition tests. The results demonstrated that MN (20 and 40 mg/kg) could markedly ameliorate the cognitive deficits in TgCRND8 mice. In addition, MN significantly increased the expression of postsynaptic density protein 93 (PSD93), PSD-95, synapsin-1, synaptotagmin-1, synaptophysin (SYN), and interleukin-10 (IL-10), while markedly reduced the protein levels of tumor necrosis factor alpha (TNF-α), IL-6, IL-1β, Aβ40, and Aβ42, and modulated the amyloid precursor protein (APP) processing and phosphorylation. Immunofluorescence showed that MN significantly suppressed the activation of microglia (Iba-1) and astrocytes (GFAP) in the hippocampus and cerebral cortex of TgCRND8 mice. Mechanistic studies revealed that MN could significantly increase the ratios of p-GSK-3β (Ser9)/GSK-3β, p-Akt (Ser473)/Akt, and p-NF-κB p65/NF-κB p65. These findings indicate that MN exerted cognitive deficits improving effects via suppressing neuroinflammation, amyloid pathology, and synaptic dysfunction through regulating the PI3K/Akt/GSK-3β and NF-κB pathways, suggesting that MN is a promising naturally occurring polyphenol worthy of further developing into a therapeutic agent for AD treatment.

Highlights

Alzheimer’s disease (AD), the most common type of dementia in the elderly population, is characterized by progressive memory loss and cognitive decline [1, 2]
The number of rearings significantly decreased in TgCRND8 mice in the open-field test, while the number of crossings did not change markedly, as compared with the wild type (WT) control group
The results demonstrated that the numbers of working memory errors (WMEs) (F ð4, 45Þ = 22:870, p < 0:001) and reference memory errors (RMEs) (F ð4, 45Þ = 9:041, p < 0:001) were effectively elevated in the Tg vehicle group when compared to the WT group

Summary

Introduction

Alzheimer’s disease (AD), the most common type of dementia in the elderly population, is characterized by progressive memory loss and cognitive decline [1, 2]. The extracellular beta-amyloid plaque (Aβ) deposits composed of Aβ peptides and the intracellular neurofibrillary tangles as a result of tau protein accumulation in the brain are the two major hallmarks of AD. Accumulating evidence suggests that neuroinflammation and the loss of neuronal synapses are observed in the early stage of AD and are associated with cognitive decline [5]. Mutation of the amyloid precursor protein (APP) induces the abnormal production of Aβ peptides by β- and γ-secretase and is believed to play a critical role in the early onset of familial AD [6].

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