Abstract
Alzheimer's disease (AD) is characterized by the brain accumulation of Aβ peptides and by the presence of neurofibrillary tangles. Aβ is believed to play an important role in AD and it has been shown that certain flavonoids can affect Aβ production. Recently, it was suggested that the Aβ lowering properties of flavonoids are mediated by a direct inhibition the β-secretase (BACE-1) activity, the rate limiting enzyme responsible for the production of Aβ peptides. Westernblots and ELISAs were employed to monitor the impact of flavonoids on amyloid precursor protein processing and Aβ production. A cell free chemoluminescent assay using human recombinant BACE-1 was used to assess the effect of flavonoids on BACE-1 activity. The effect of flavonoids on NFκB activation was determined by using a stable NFκB luciferase reporter cell line. Molecular docking simulations were performed to predict the binding of flavonoids to the BACE-1 catalytic site. Real time quantitative PCR was used to determine the effect of flavonoids on BACE-1 transcription. We show in a cell free assay that flavonoids are only weak inhibitors of BACE-1 activity. Docking simulation studies with different BACE-1 structures also suggest that flavonoids are poor BACE-1 inhibitors as they appear to adopt various docking poses in the active site pocket and have weak docking scores that differ as a function of the BACE-1 structures studied. Moreover, a weak correlation was observed between the effect of flavonoids on Aβ production in vitro and their ability to lower BACE-1 activity suggesting that the Aβ lowering properties of flavonoids in whole cells are not mediated via direct inhibition of BACE-1 activity. We found however a strong correlation between the inhibition of NFκB activation by flavonoids and their Aβ lowering properties suggesting that flavonoids inhibit Aβ production in whole cells via NFκB related mechanisms. As NFκB has been shown to regulate BACE-1 expression, we show that NFκB lowering flavonoids inhibit BACE-1 transcription in human neuronal SH-SY5Y cells. Altogether, our data suggest that flavonoids inhibit Aβ and sAPPβ production by regulating BACE-1 expression and not by directly inhibiting BACE-1 activity.
Highlights
Alzheimer’s disease (AD) is a major health concern among the aging population and is the most prevalent form of dementia
As BACE-1 is the rate limiting enzyme responsible for Aβ production and is considered to be a prime target for AD, we further investigated whether flavonoids can lower Aβ
A decreased amyloid precursor protein (APP)-CTFβ production as well as an inhibition of sAPPβ secretion was observed for luteolin, quercetin, apigenin and kaempferol (Figure 2) suggesting that these flavonoids lower Aβ production by impacting the β-cleavage of APP
Summary
Alzheimer’s disease (AD) is a major health concern among the aging population and is the most prevalent form of dementia. While the cause of the disease remains uncertain, the extracellular senile plaques and the intracellular neurofibrillary tangles constitute the two major neuropathological hallmarks present in the brains of AD patients. Neurofibrillary tangles contain hyperphosphorylated microtubule-associated protein tau, while senile plaques contain a core of β-amyloid (Aβ) peptides. The major β-secretase is an aspartyl protease termed BACE-1 (β-site APP cleaving enzyme) [2,3,4]. BACE-1 cleaves APP within the extracellular domain of APP, resulting in the secretion of the large ectodomain (APPsβ) and generating a membrane-tethered C-terminal fragment CTFβ or C99 which serves as a substrate for γ-secretase [5]. The multimeric γ-secretase complex cleaves at multiple sites within the transmembranous CTFβ generating C-terminally heterogeneous Aβ peptides ranging between 38 to 43 amino-acid residues in length that are secreted [6]. Genetic ablation of BACE-1 completely abolishes Aβ production, establishing BACE-1 as the major neuronal enzyme responsible for initiating the amyloidogenic processing of APP [7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
