Modified Huang-Lian-Jie-Du Decoction Ameliorates Aβ Synaptotoxicity in a Murine Model of Alzheimer's Disease.

Linchao Qian,Wenlong Zhang,Xiangdong Sun,Zhichao Peng,Ting Du,Lei Wen,Yunlong Zhang,Pingyi Xu,Chaojun Chen,Yan Liu,Weiye Lu,Xiaoqin Zhu,Shuqiong Huang

doi:10.1155/2019/8340192

Abstract

Alzheimer's disease (AD) is a common neurodegenerative disease, characterized by cognitive dysfunction; however, the therapeutic strategies are not fully understood. Huang-Lian-Jie-Du-Decoction (HLJDD) is a famous traditional Chinese herbal formula that has been widely used clinically to treat dementia. Recently, according to previous study and our clinical practice, we generate a new modification of HLJDD (named modified-HLJDD). In this study, we indicated that modified-HLJDD attenuated learning and memory deficiencies in Aβ1-42 oligomer-induced AD model, and we confirmed the exact metabolites in modified-HLJDD solution, as compared with HLJDD by UHPLC-Q-TOF-MS. Using GC-Q-TOF/MS-based metabolomics, we identified adenosine as the potential significant metabolite, responsible for modified-HLJDD regulating energy metabolism and synaptic plasticity in AD model. We also revealed that the potential underlying mechanism of modified-HLJDD in AD model may involve NMDA receptor-mediated glutamatergic transmission and adenosine/ATPase/AMPK cascade. Moreover, we also indicated the differential gut microbiota which mainly involved Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria at the phylum level upon modified-HLJDD treatment in AD model. Based on the correlation of metabolomic analysis with microbiome analysis, we clarified that Dorea is the most affected microbiota with adenosine upon modified-HLJDD treatment in AD model. Thus, our study suggests that modified-HLJDD may serve as a potential therapeutic drug in treating AD.

Highlights

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, causing memory loss and cognitive dysfunction
These results indicate that modified-HLJDD is more effective in attenuating memory deficiency in the Aβ1-42 oligomer-treated AD model
We found that hippocampal concentrations of adenosine and the ratio of 4-HPP/L-tyrosine were decreased in the Aβ1-42 oligomer-treated AD model, while modified-HLJDD treatment increased their concentrations in the AD model (Figures 5(a) and 5(d))

Summary

Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, causing memory loss and cognitive dysfunction. Extracellular senile plaques and phosphorylated tauassociated intraneuronal neurofibrillary tangles (NFTs) are the two classical pathologic hallmarks in AD. Senile plaques comprise amyloid-β (Aβ), which is released from amyloid precursor protein (APP) after the sequential cleavages of APP by β- and γ-secretases. Oligomeric Aβ has been proven to disrupt glutamatergic receptor activity and impair long-term potentiation (LTP), a form of synaptic plasticity [2]. Oligomeric Aβ can induce synaptic loss via Oxidative Medicine and Cellular Longevity disruption of glutamatergic receptors, calcium homeostasis, and mitochondrial dynamics [4,5,6]. Aβ plays a crucial role in the etiology of AD, and Aβ-induced synaptic dysfunction mimics the early stages of AD pathogenesis [7]. The underlying mechanism of Aβ-induced synaptic collapse in the early stages of AD is still unclear

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