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Flavonoids lower Alzheimer's A? production via an NF?B dependent mechanism.

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. Westernblots 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 NF?B activation by flavonoids and their A? lowering properties suggesting that flavonoids inhibit A? production in whole cells via NF?B related mechanisms. As NF?B has been shown to regulate BACE-1 expression, we show that NF?B 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.

SUBMITTER: Paris D

PROVIDER: S-EPMC3124791 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Flavonoids lower Alzheimer's Aβ production via an NFκB dependent mechanism.

Paris Daniel D Mathura Venkat V Ait-Ghezala Ghania G Beaulieu-Abdelahad David D Patel Nikunj N Bachmeier Corbin C Mullan Michael M

Bioinformation 20110606 6

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 emplo ...[more]

PMID: 21738321

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Flavonoids lower Alzheimer's A? production via an NF?B dependent mechanism.

Publications

Flavonoids lower Alzheimer's Aβ production via an NFκB dependent mechanism.

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