Fuzhisan ameliorates cognitive ability in Alzheimer's disease by p62 and related autophagy regulatory pathways

Zhaoxu Zhang; Shuangmei Zhang; Shen Liu; Yang He; Anrong Wang

doi:10.1016/j.brainres.2024.149436

Fuzhisan ameliorates cognitive ability in Alzheimer's disease by p62 and related autophagy regulatory pathways

Brain Res. 2024 Dec 28:1849:149436. doi: 10.1016/j.brainres.2024.149436. Online ahead of print.

Authors

Zhaoxu Zhang¹, Shuangmei Zhang², Shen Liu³, Yang He¹, Anrong Wang⁴

Affiliations

¹ Department of Neurology, Peking University People's Hospital, Beijing 100044, PR China.
² Department of Pain Rehabilitation Rehabilitation, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 310022, PR China.
³ Department of Rehabilitation Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 251412, PR China; Department of Neurology of TCM, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, PR China.
⁴ Department of Traditional Chinese Medicine, The First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital), Jinan 250014, PR China. Electronic address: 13864031500@163.com.

PMID: 39736370
DOI: 10.1016/j.brainres.2024.149436

Abstract

Background: Maintaining autophagic homeostasis has been proved to play an important role in Alzheimer's disease.

Object: The aim of this study was to investigate the effect of Fuzhisan(FZS) on autophagic function in Alzheimer's disease and to elucidate its potential mechanism through the P62 regulatory pathways.

Methods: FZS was extracted by water extraction-rotary evaporation method. The novel object recognition test, morris water maze test and Y maze test were used to observe the cognitive and memory ability of APP/PS1 mice. The effects of FZS on the ultrastructure of mice hippocampus were examined by transmission electron microscopy. Molecular level changes were also further detected, including Aβ deposition, tau hyperphosphorylation, SOD, CAT and autophagy related proteins (p62, Nrf2, keap1, mTOR, LC3II/I, Beclin1, Atgs).

Results: FZS could alleviate memory and cognitive impairment in APP/PS1 mice, increase the autophagic vesicles and organelle abundance in hippocampus. FZS also reduced the levels of Aβ and tau hyperphosphorylation in the hippocampus of model mice, upregulated the levels of SOD, CAT and autophagy related proteins (Nrf2, LC3II/LC3I, Beclin1, Atg7 and Atg12) as well as downregulated the expression of P62, keap1 and p-mTOR/mTOR proteins. Co-Ip results showed that FZS elevated the levels of p62/LC3 and P62-keap1-Nrf2 complex, but decreased the P62 and keap1 association.

Conclusion: Our findings indicate that FZS may affect autophagy function and oxidative stress by regulating P62 and related pathways to promote the clearance of Aβ and phosphorylated tau, thereby improving the cognitive ability of AD, which provided a novel perspective for exploring the potential mechanism of FZS upon AD.

Keywords: Alzheimer’s disease; Autophagy; Fuzhisan (FZS); P62.