Substrate-Specific Activation of α-Secretase by 7-Deoxy-Trans-Dihydronarciclasine Increases Non-Amyloidogenic Processing of β-Amyloid Protein Precursor.

Yoon Sun Chun,Hyun Ok Yang,Sungkwon Chung,Oh Hoon Kwon,Yoon Young Cho,Dong Zhao

doi:10.3390/molecules25030646

Abstract

Accumulation of β-amyloid (Aβ) in the brain has been implicated in the pathology of Alzheimer’s disease (AD). Aβ is produced from the Aβ precursor protein (APP) through the amyloidogenic pathway by β-, and γ-secretase. Alternatively, APP can be cleaved by α-, and γ-secretase, precluding the production of Aβ. Thus, stimulating α-secretase mediated APP processing is considered a therapeutic option not only for decreasing Aβ production but for increasing neuroprotective sAPPα. We have previously reported that 7-deoxy-trans-dihydronarciclasine (E144), the active component of Lycoris chejuensis, decreases Aβ production by attenuating APP level, and retarding APP maturation. It can also improve cognitive function in the AD model mouse. In this study, we further analyzed the activating effect of E144 on α-secretase. Treatment of E144 increased sAPPα, but decreased β-secretase products from HeLa cells stably transfected with APP. E144 directly activated ADAM10 and ADAM17 in a substrate-specific manner both in cell-based and in cell-free assays. The Lineweaver–Burk plot analysis revealed that E144 enhanced the affinities of A Disintegrin and Metalloproteinases (ADAMs) towards the substrate. Consistent with this result, immunoprecipitation analysis showed that interactions of APP with ADAM10 and ADAM17 were increased by E144. Our results indicate that E144 might be a novel agent for AD treatment as a substrate-specific activator of α-secretase.

Highlights

Alzheimer’s disease (AD) is characterized by the accumulation of extracellular senile amyloid plaques and intracellular neurofibrillary tangles composed of hyper-phosphorylated tau [1,2].Hyperphosphorylated tau aggregates into paired helical filaments, which form the neurofibrillary tangles and affect neurons
When cells were incubated with E144 for 1 h, the level of sAPPα was significantly increased by 29.7% ± 8.4%
Since E144 decreased the amyloidogenic processing of Aβ precursor protein (APP), we examined the effect of E144 on Aβ levels

Summary

Introduction

Alzheimer’s disease (AD) is characterized by the accumulation of extracellular senile amyloid plaques and intracellular neurofibrillary tangles composed of hyper-phosphorylated tau [1,2]. Hyperphosphorylated tau aggregates into paired helical filaments, which form the neurofibrillary tangles and affect neurons. Neurotoxic β-amyloid (Aβ) peptides are the dominant components of senile plaques that play a central role in the Molecules 2020, 25, 646; doi:10.3390/molecules25030646 www.mdpi.com/journal/molecules. The aggregation of Aβ provokes neuronal dysfunction, memory impairment, and synaptic damage [4,5]. APP can be cleaved by β-secretase producing soluble ectodomain fragment (sAPPβ) and C-terminal fragment (CTF), C99. C99 is further cleaved by γ-secretase to yield several Aβ species with different length and APP intracellular domain (AICD)

Methods

Results

Conclusion