RhoA/Rock2/Limk1/cofilin1 pathway is involved in attenuation of neuronal dendritic spine loss by paeonol in the frontal cortex of D-galactose and aluminum-induced Alzheimer’s disease-like rat model

Fei Han,Hui Xu,Jun-Xian Shen,Jing-Jing Chen,Ya-Fei Cai,Chuan Pan,Xiu-Ling Zhu,Zong-Hao Yu,Ya-Ping Lu

doi:10.21307/ane-2020-021

Abstract

Alzheimer's disease (AD) has become the most prevalent neurodegenerative disorder. Given the pathogenesis of AD is unclear, there is currently no drug approved to halt or delay the progression of AD. Therefore, it is pressing to explore new targets and drugs for AD. In China, polyphenolic Chinese herbal medicine has been used for thousands of years in clinical application, and no toxic effects have been reported. In the present study, using D‑galactose and aluminum‑induced rat model, the effects of paeonol on AD were validated via the Morris water maze test, open field test, and elevated plus maze test. Neuronal morphology in frontal cortex was assessed using ImageJ's Sholl plugin and RESCONSTRUCT software. RhoA/Rock2/Limk1/cofilin1 signaling pathway‑related molecules were determined by Western blotting. Cofilin1 and p‑cofilin1 were analyzed by immunofluorescence. Results showed that pre‑treatment with paeonol attenuated D‑galactose and aluminum‑induced behavioral dysfunction and AD‑like pathological alterations in the frontal cortex. Accompanied by these changes were the alterations in the dendrite and dendritic spine densities, especially the mushroom‑type and filopodia‑type spines in the apical dendrites, as well as actin filaments. In addition, the activity and intracellular distribution of cofilin1 and the molecules RhoA/Rock2/Limk1 that regulate the signaling pathway for cofilin1 phosphorylation have also changed. Our data suggests that paeonol may be through reducing Aβ levels to alleviate the loss of fibrillar actin and dendrites and dendritic spines via the Rho/Rock2/Limk1/cofilin1 signaling pathway in the frontal cortex, and ultimately improving AD‑like behavior.

Highlights

Dementia is one of the major causes of disability and dependency among older people worldwide
One‐way ANOVA showed that paeonol significantly relieved D‐ga‐ lactose and aluminum‐induced reduction in the number of squares crossed (F2,25=25.012, P
We found that paeonol atten‐ uated D‐galactose and aluminum‐induced behavioral dysfunction and Alzheimer disease (AD)‐like pathological alterations in the frontal cortex

Summary

Introduction

Dementia is one of the major causes of disability and dependency among older people worldwide. There are nearly 10 million new cases (WHO, 2019). Alzheimer disease (AD) is the most common form of de‐ mentia and may account for 60–70% of cases (Tang et al, 2016). The early clinical symptoms of the disease are mainly cognitive impairment such as memory and visuo‐spatial skills, and gradually worsen, accom‐. Panied by emotional behavioral reactions such as de‐ pression, anxiety, and decreased activity (Lyketsos et al, 2011; Ameen-Ali et al, 2017; Götz et al, 2018). The typical histopathological hallmarks of AD are the aggregation of amyloid‐beta in extracellular senile plaques, accumulation of tau in intracellular neurofibril‐ lary tangles, and neuron loss, in the brain especially in hippocampus and frontal cortex (Hyman et al, 2012; Grontvedt et al, 2018; Alzheimer’s Association, 2019).

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