Electroacupuncture Protects Cognition by Regulating Tau Phosphorylation and Glucose Metabolism via the AKT/GSK3β Signaling Pathway in Alzheimer's Disease Model Mice.

Anping Xu,Xiaochen Yuan,Yinshan Tang,Qingtao Zeng,You Zhou,Xin Wang,Zhigang Li

doi:10.3389/fnins.2020.585476

Abstract

BackgroundAlzheimer’s disease (AD) is mainly manifested as a continuous and progressive decline in cognitive ability. Neurofibrillary tangles (NFTs) are pathological hallmarks of AD and due to accumulated phosphorylated Tau. Glycogen synthase kinase-3β (GSK3β), as a major Tau kinase and a downstream target of the serine protein kinase B (AKT) signaling pathway, can regulate Tau phosphorylation in AD. Importantly, the AKT/GSK3β signaling pathway is involved in glucose metabolism, and abnormal glucose metabolism is found in the AD brain. Numerous studies have shown that electroacupuncture (EA), which is thought to be a potential complementary therapeutic approach for AD, can protect cognitive ability to a certain extent.ObjectiveThe purpose of this experiment was to investigate whether the protective and beneficial mechanism of EA on cognition was mediated by the AKT/GSK3β signaling pathway, thereby improving glucose metabolism and Tau phosphorylation in the brain.MethodsEA was applied to the Baihui (GV20) and Yintang (GV29) acupoints of 6-month-old amyloid precursor protein (APP)/presenilin-1 (PS1) mice for 20 min, and then quickly prick Shuigou (GV26) acupoint. The intervention was performed once every other day for 28 days. The Morris water maze (MWM) test was performed on C57BL/6N (Non-Tg) mice, APP/PS1 (Tg) mice and EA-treated Tg (Tg + EA) mice to evaluate the effect of EA therapy on cognitive function. 18F-FDG positron emission tomography (PET), immunohistochemistry, and western blotting (WB) were used to investigate the possible mechanism underlying the effect of EA on AD.ResultsEA treatment significantly improved the cognition of APP/PS1 mice and the glucose uptake rate in the hippocampus. Furthermore, EA inhibited the phosphorylation of Tau (Ser199 and Ser202) proteins by inducing AKT (Ser473) and GSK3β (Ser9) phosphorylation.ConclusionThese results demonstrate that EA intervention protects cognition by enhancing glucose metabolism and inhibiting abnormal phosphorylation of Tau protein in the AD model mice, and the AKT/GSK3β pathway might play an irreplaceable role in the regulation process.

Highlights

According to the World Alzheimer Report 2018, there is one new case of dementia every 3 s across the world
We studied the effects of EA on Tau and glucose metabolism separately but neglected to explore the connection between its effects on these processes
The results showed that EA had no significant differences in the total protein expressions of AKT or Glycogen synthase kinase-3β (GSK3β) in the hippocampus among groups

Summary

Introduction

According to the World Alzheimer Report 2018, there is one new case of dementia every 3 s across the world. A systematic analysis of the global burden of disease found that dementia was the fastest-growing cause of death between 2005 and 2015, increasing by 40% (GBD 2015 Mortality and Causes of Death Collaborators, 2016). The main clinical manifestations of Alzheimer’s disease (AD) are progressive episodic memory disorder, cognitive dysfunction, and decreased ability in activities of daily living. There are currently two types of drugs available, cholinesterase inhibitors and NMDA receptor antagonists, both of which aim to treat some of the symptoms of AD but cannot prevent the progression of the disease (Alzheimer Disease Agents, 2012). Alzheimer’s disease (AD) is mainly manifested as a continuous and progressive decline in cognitive ability. The AKT/GSK3β signaling pathway is involved in glucose metabolism, and abnormal glucose metabolism is found in the AD brain. Numerous studies have shown that electroacupuncture (EA), which is thought to be a potential complementary therapeutic approach for AD, can protect cognitive ability to a certain extent

Methods

Results

Conclusion