Dendrobium nobile Lindl. Alkaloids Decreases the Level of Intracellular β-Amyloid by Improving Impaired Autolysosomal Proteolysis in APP/PS1 Mice.

Jing Nie,Yan-Liu Lu,Yong Tian,Yu Zhang,Jing-Shan Shi,Li-Sheng Li,Wen-Jin Yang,Lin-Shan Jiang

doi:10.3389/fphar.2018.01479

Abstract

As the major degradation pathway for long-lived proteins and organelles, macroautophagy is a decisive factor for the survival and longevity of cells. The existing evidence indicates that the disruption of substrate proteolysis in autolysosomes is the main mechanism underlying autophagy failure in Alzheimer’s disease (AD). Thus, the restoration of normal lysosomal proteolysis and autophagy efficiency is a novel therapeutic strategy in the treatment of AD. In this study, 9-month-old APPswe/PS1ΔE9 transgenic (APP/PS1) mice were administered Dendrobium nobile Lindl. alkaloids (DNLA, 40 and 80 mg/kg) or Metformin (80 mg/kg), and age-matched wild-type mice were administered an isovolumic vehicle orally once a day for 4 months. The results demonstrated that DNLA significantly improved learning and memory function in APP/PS1 transgenic mice in the Morris water maze. Furthermore, DNLA could increase the expression of the v-ATPase A1 subunit to facilitate lysosomal acidification, prompt the dissociation of the cation independent-mannose-phosphate receptor from cathepsin (cat) D, promote the proteolytic maturation of cat D, increase the degradation of accumulated autophagic vacuoles (AVs) and β-amyloid (Aβ) contained in the AVs, and alleviate neuronal and synaptic injury. These findings demonstrate that DNLA improves learning and memory function in APP/PS1 mice, and the mechanisms appear to be due to the promotion of intracellular Aβ degradation by increasing the protein level of v-ATPase A1 and then improving autolysosomal acidification and proteolysis.

Highlights

Alzheimer’s disease (AD) is a common age-related neurodegenerative disorder characterized by extracellular senile plaques, intracellular neurofibrillary tangles, and neuronal degeneration along with significant synaptic loss (Selkoe, 2002; Cavallucci et al, 2012)
It was demonstrated that Aβ was generated in autophagic vacuoles (AVs), which abnormally aggregated in the affected neurons during macroautophagy (Yu et al, 2005)
Abnormal degradation of AVs may be a major reason for the reduction of Aβ clearance, suggesting that restoring normal lysosomal proteolysis and autophagy efficiency may promote the clearance of intracellular Aβ, and indicating the potential of autophagy modulation as a therapeutic strategy

Summary

Introduction

Alzheimer’s disease (AD) is a common age-related neurodegenerative disorder characterized by extracellular senile plaques, intracellular neurofibrillary tangles, and neuronal degeneration along with significant synaptic loss (Selkoe, 2002; Cavallucci et al, 2012). A comparison of the generation and clearance of CNS Aβ in patients with symptomatic AD and in normal individuals indicated that the average production rates of Aβ1−40 and Aβ1−42 did not differ between the control group and the AD group. Current evidence indicates that substrate proteolysis within autolysosomes is damaged in the brains of AD patients, resulting in the massive accumulation of incompletely digested substrates including Aβ contained in AVs (Nixon and Yang, 2011). Abnormal degradation of AVs may be a major reason for the reduction of Aβ clearance, suggesting that restoring normal lysosomal proteolysis and autophagy efficiency may promote the clearance of intracellular Aβ, and indicating the potential of autophagy modulation as a therapeutic strategy

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