Abstract
Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the enzyme involved in the abnormal production of the amyloidogenic peptide Aβ, one of the major causes of histological hallmarks of Alzheimer’s disease (AD). Thus, BACE1 represents a key target protein in the development of new potential target for the prevention and treatment of AD. In this study, in vitro anti-AD activity of biochanin A, a dietary isoflavone found in legumes and most notably red clover, were evaluated via human recombinant BACE1 inhibition assay, as well as enzyme kinetic and molecular docking predictions. Enzyme-based assays revealed that biochanin A exhibited a non-competitive inhibitory effect on BACE1 with an IC50 value of 28 μM and a Ki of 43 μM. In addition, docking simulation results demonstrated that ASN37, SER35, SER36, TRP76, and ARG128 residues of BACE1 interacted with biochanin A. Moreover, the binding energy of biochanin A was negative (−8.4 kcal/mol), indicating that it might potentiate a strong binding between the compound and the allosteric site of BACE1, resulting in further effective BACE1 inhibition. The present novel findings raise the possibility that biochanin A may be used as a preventative, developed into a therapeutic agent for AD, or both.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder presenting with symptoms such as memory loss and disruption in judgment, reasoning, and emotional stability
A Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) assay kit was purchased from Pan Vera (Madison, WI, USA). α-Secretase (TACE) and substrates were obtained from R & D systems (Minneapolis, MN, USA)
We investigated whether biochanin A has BACE1 inhibitory activity by an in vitro BACE1
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder presenting with symptoms such as memory loss and disruption in judgment, reasoning, and emotional stability. The predominant pathological hallmarks of the disease are amyloid plaques, i.e., extracellular deposits of polymerized amyloid-β peptides (Aβ), and intracellular aggregates of misfolded tau protein [1,2]. The produced Aβ is normally secreted, and can accumulate and form insoluble aggregates [4,5]. (BACE1) is the main form of β-secretase that cleaves APP to generate Aβ [7]. The unique and essential role of BACE1 for the generation of Aβ has been convincingly shown in mice where both alleles have been ablated by genetic means. These mice neither formed Aβ, nor cleaved APP at the known
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