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Title

Flavonoids lower Alzheimer's A production via an NFkB dependent mechanism

 

Authors

Daniel Paris, Venkat Mathura*, Ghania Ait-Ghezala, David Beaulieu-Abdelahad, Nikunj Patel, Corbin Bachmeier, Michael Mullan

 

Affiliation

Roskamp Institute, 2040 Whitfield Avenue, Sarasota, Florida 34243, USA

 

Email

vmathura@rfdn.org; *Corresponding author

 

Article Type

Hypothesis

 

Date

Received May 28, 2011; Accepted May 29, 2011; Published June 06, 2011

 

Abstract

Alzheimer's disease (AD) is characterized by the brain accumulation of A peptides and by the presence of neurofibrillary tangles. A is believed to play an important role in AD and it has been shown that certain flavonoids can affect A production. Recently, it was suggested that the A lowering properties of flavonoids are mediated by a direct inhibition the -secretase (BACE-1) activity, the rate limiting enzyme responsible for the production of A peptides. Western-blots and ELISAs were employed to monitor the impact of flavonoids on amyloid precursor protein processing and A 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 NF?B activation was determined by using a stable NF?B 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 A production in vitro and their ability to lower BACE-1 activity suggesting that the A 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 NFkB activation by flavonoids and their A lowering properties suggesting that flavonoids inhibit A production in whole cells via NFkB related mechanisms. As NFkB has been shown to regulate BACE-1 expression, we show that NFkB lowering flavonoids inhibit BACE-1 transcription in human neuronal SH-SY5Y cells. Altogether, our data suggest that flavonoids inhibit A and sAPP production by regulating BACE-1 expression and not by directly inhibiting BACE-1 activity.

 

Citation

Paris et al. Bioinformation 6(6): 229-236 (2011)

Edited by

P Kangueane

 

ISSN

0973-2063

 

Publisher

Biomedical Informatics

 

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.