Dihydroartemisinin Ameliorates Learning and Memory in Alzheimer's Disease Through Promoting Autophagosome-Lysosome Fusion and Autolysosomal Degradation for Aβ Clearance.

Yueyang Zhao,Min Feng,Zhimin Long,Yuanjie Liu,Yimin Li,Kejian Wang,Tingting Jiang,Ya Ding,Xuehua Peng,Jiajun Liu,Guiqiong He

doi:10.3389/fnagi.2020.00047

Abstract

Dihydroartemisinin (DHA) is an active metabolite of sesquiterpene trioxane lactone extracted from Artemisia annua, which is used to treat malaria worldwide. DHA can activate autophagy, which is the main mechanism to remove the damaged cell components and recover the harmful or useless substances from eukaryotic cells and maintain cell viability through the autophagy lysosomal degradation system. Autophagy activation and autophagy flux correction are playing an important neuroprotective role in the central nervous system, as they accelerate the removal of toxic protein aggregates intracellularly and extracellularly to prevent neurodegenerative processes, such as Alzheimer’s disease (AD). In this study, we explored whether this mechanism can mediate the neuroprotective effect of DHA on the AD model in vitro and in vivo. Three months of DHA treatment improved the memory and cognitive impairment, reduced the deposition of amyloid β plaque, reduced the levels of Aβ40 and Aβ42, and ameliorated excessive neuron apoptosis in APP/PS1 mice brain. In addition, DHA treatment increased the level of LC3 II/I and decreased the expression of p62. After Bafilomycin A1 and Chloroquine (CQ) blocked the fusion of autophagy and lysosome, as well as the degradation of autolysosomes (ALs), DHA treatment increased the level of LC3 II/I and decreased the expression of p62. These results suggest that DHA treatment can correct autophagic flux, improve autophagy dysfunction, inhibit abnormal death of neurons, promote the clearance of amyloid-β peptide (Aβ) fibrils, and have a multi-target effect on the neuropathological process, memory and cognitive deficits of AD.

Highlights

Alzheimer’s disease (AD) has been known as one of the neurodegenerative diseases, manifested by chronic and progressive memory and cognitive deficits (Luheshi et al, 2008)
The experiments were carried out utilizing male APPswe/PSEN1dE9 double-transgenic (APP/Presenilin 1 (PS1)) mice and non-transgenic littermates that were purchased from the Biomedical Research Institute of Nanjing University (Nanjing, China)
The results showed that compared with the control group, the levels of amyloid precursor protein (APP) and β-site APP cleaving enzyme (BACE1) protein were down-regulated after DHA treatment, indicating that amyloid-β peptide (Aβ) production was reduced

Summary

Introduction

Alzheimer’s disease (AD) has been known as one of the neurodegenerative diseases, manifested by chronic and progressive memory and cognitive deficits (Luheshi et al, 2008). AD manifests via synaptic abnormalities, neuronal degeneration as well as the deposition of extracellular amyloid plaques and intraneuronal neurofibrillary tangles, which lead to a decline in memory and other cognitive functions. Excessive production and degradation of Aβ in cells lead to an imbalance and accumulation of Aβ metabolism. It has been found that extracellular Aβ is only the result of its toxic effect on cells, and the accumulation of intracellular Aβ is the fundamental factor leading to the cytotoxic effects (Esquerda-Canals et al, 2017). Autophagy in healthy neurons is characterized by its high efficiency and continuous activation but low level (Boland et al, 2008) that accelerates the clearance of toxic and damaged intraneuronal and extracellular protein aggregates in lysosomes digestion system (Fecto et al, 2014). It has been reported that autophagy acts as a ‘‘double-edged sword’’ in the development of AD (Martinet et al, 2009; Choi et al, 2018; Hamano et al, 2018)

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Conclusion