Abstract
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease, distinctively characterized by senile plaques, neurofibrillary tangles, and synaptic loss, finally resulting in neuronal death. β-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) and cholinesterases have been identified as therapeutic targets for AD, and the discovery of their inhibitors is of critical importance for developing preventive strategies for AD. To discover natural multi-target compounds possessing BACE1, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory properties, major citrus flavanones including hesperetin, naringenin, and hesperidin were evaluated. In vitro anti-AD activities were performed via BACE1 and cholinesterases inhibition assays, as well as enzyme kinetic predictions. For the design of potential inhibitors of AD-related enzymes, molecular docking analysis was performed. Based on the biological evaluation, hesperidin demonstrated the best inhibitory properties toward BACE1, AChE, and BChE, with IC50 values of 10.02 ± 1.12, 22.80 ± 2.78, and 48.09 ± 0.74 µM, respectively. Kinetic studies revealed that all tested compounds were found to be noncompetitive inhibitors against BACE1 and cholineseterases. In addition, molecular docking studies of these compounds demonstrated negative binding energies for BACE1, AChE, and BChE, indicating high affinity and tight binding capacity for the target enzymes. The present study suggested that the selected citrus flavanones could act together as multiple inhibitors of BACE1, AChE, and BChE, indicating preventive and therapeutic potential against AD.
Highlights
Alzheimer0 s disease (AD), characterized by the appearance of senile plaques and neurofibrillary tangles, as well as a loss of cholinergic neurons, is the most prevalent form of dementia [1]
Molecules 2018, 23, 1509 protein levels and activity are elevated in sporadic Alzheimer’s disease (AD) brains, and that BACE1 levels are upregulated under stress conditions such as oxidative stress, cerebral ischemia, and hypoxia, all of which are associated with increased AD incidence [5,6,7]
The IC50 value of hesperidin was similar to that of resveratrol, which was used as a positive control
Summary
Alzheimer0 s disease (AD), characterized by the appearance of senile plaques and neurofibrillary tangles, as well as a loss of cholinergic neurons, is the most prevalent form of dementia [1]. Senile plaques contain a major protein known as the β-amyloid protein (Aβ), whereas neurofibrillary tangles are insoluble twisted fibers inside nerve cells, consisting of hyper-phosphorylated tau protein [2]. The “amyloid cascade hypothesis” has emerged as the principal mechanism of AD pathology, with in vivo evidence having demonstrated that aggregated Aβ induces neurofibrillary tangle formation as well as neuronal death [3,4]. Aβ peptide is generated by sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretase. Studies show that β-secretase (β-site amyloid precursor protein cleaving enzyme 1, BACE1). Given that BACE1 is the initial and rate-limiting step in
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