Abstract
Alzheimer′s disease (AD) is one of the most common neurodegenerative diseases with a multifactorial nature. β-Secretase (BACE1) and acetylcholinesterase (AChE), which are required for the production of neurotoxic β-amyloid (Aβ) and the promotion of Aβ fibril formation, respectively, are considered as prime therapeutic targets for AD. In our efforts towards the development of potent multi-target, directed agents for AD treatment, major phlorotannins such as eckol, dieckol, and 8,8′-bieckol from Ecklonia cava (E. cava) were evaluated. Based on the in vitro study, all tested compounds showed potent inhibitory effects on BACE1 and AChE. In particular, 8,8′-bieckol demonstrated the best inhibitory effect against BACE1 and AChE, with IC50 values of 1.62 ± 0.14 and 4.59 ± 0.32 µM, respectively. Overall, kinetic studies demonstrated that all the tested compounds acted as dual BACE1 and AChE inhibitors in a non-competitive or competitive fashion, respectively. In silico docking analysis exhibited that the lowest binding energies of all compounds were negative, and specifically different residues of each target enzyme interacted with hydroxyl groups of phlorotannins. The present study suggested that major phlorotannins derived from E. cava possess significant potential as drug candidates for therapeutic agents against AD.
Highlights
Alzheimer0 s disease (AD) is a progressive and irreversible neurodegenerative disorder with characteristic features of cognitive dysfunction, memory impairment, and behavior disturbances.The neuropathological hallmarks of Alzheimer s disease (AD) patients are the presence of extracellular deposits of amyloid plaques and intracellular filamentous neurofibrillary tangles in the brain [1]
The neuropathological hallmarks of AD patients are the presence of extracellular deposits of amyloid plaques and intracellular filamentous neurofibrillary tangles in the brain [1]
The “amyloid hypothesis” has arisen as the major pathological mechanism in AD, and the evidence from transgenic mice models revealed that amyloid-β peptide (Aβ) triggered tau phosphorylation and neurofibrillary tangles formation [2]
Summary
Alzheimer0 s disease (AD) is a progressive and irreversible neurodegenerative disorder with characteristic features of cognitive dysfunction, memory impairment, and behavior disturbances. The neuropathological hallmarks of AD patients are the presence of extracellular deposits of amyloid plaques and intracellular filamentous neurofibrillary tangles in the brain [1]. Amyloid plaques and neurofibrillary tangles are aggregates of amyloid-β peptide (Aβ) and hyperphosphorylated tau protein, respectively. The “amyloid hypothesis” has arisen as the major pathological mechanism in AD, and the evidence from transgenic mice models revealed that Aβ triggered tau phosphorylation and neurofibrillary tangles formation [2]. Aβ is generated by the sequential proteolytic cleavage of two aspartic proteases, β- and γ–secretase, in the amyloidogenic pathway. Mar. Drugs 2019, 17, 91; doi:10.3390/md17020091 www.mdpi.com/journal/marinedrugs
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