Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease conceptualized as a clinical-biological neurodegenerative construct where amyloid-beta pathophysiology is supposed to play a role. The loss of cognitive functions is mostly characterized by the rapid hydrolysis of acetylcholine by cholinesterases including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Moreover, both enzymes are responsible for non-catalytic actions such as interacting with amyloid β peptide (Aβ) which further leads to promote senile plaque formation. In searching for a natural cholinesterase inhibitor, the present study focused on two isocoumarines from hydrangea, thunberginol C (TC) and hydrangenol 8-O-glucoside pentaacetate (HGP). Hydrangea-derived compounds were demonstrated to act as dual inhibitors of both AChE and BChE. Furthermore, the compounds exerted selective and non-competitive mode of inhibition via hydrophobic interaction with peripheral anionic site (PAS) of the enzymes. Overall results demonstrated that these natural hydrangea-derived compounds acted as selective dual inhibitors of AChE and BChE, which provides the possibility of potential source of new type of anti-cholinesterases with non-competitive binding property with PAS.

Highlights

  • Published: 17 January 2021Alzheimer’s disease (AD) is a neurodegenerative disease characterized by severe cognitive impairment [1]

  • A beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) fluorescence resonance energy transfer (FRET) assay kit was purchased from Pan Vera (Madison, WI, USA)

  • The results demonstrated that thunberginol C (TC) and hydrangenol 8-O-glucoside pentaacetate (HGP) did not exhibit significant inhibition against serine proteases and BACE1, indicating that both compounds selectively inhibit

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Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by severe cognitive impairment [1]. Cholinergic deficit underlying the memory and cognitive decline is connected with decreased levels of the neurotransmitter, acetylcholine (ACh). Acetylcholinesterase (AChE), an important component of cholinergic synapses, is responsible for the hydrolysis of ACh [2]. The enzyme is found principally at neuromuscular junctions and cholinergic synapses in high concentrations. Butyrylcholinesterase (BChE) is a non-specific type of cholinesterase involved in the hydrolysis of ACh, which is ubiquitously expressed in liver, blood serum, pancreas and associated with glial and endothelial cells in the brain [3]. Because of low expression in brain, the importance of BChE was underestimated in neurodegenerative diseases such as AD [4]

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