Alzheimers disease (AD) is characterized by the brain accumulation of A peptides a nd y the presence of neurofi rillary tangles.

A is elieved to play an important role in AD and it has een shown that certain flavonoids can affect A production . Recently, it was suggested that the A lowering properties of flavonoids are med iated y a direct inhi ition the -secretase (BACE-1) activity, the rate limiting enzyme responsi le for the production of A peptides. Western lots and ELISAs were employed to monitor the impact of flavonoids on amyloid precursor protein proce ssing and A production. A cell free chemoluminescent assay using human recom inan t BACE-1 was used to assess the effect of flavonoids on BACE-1 activity. The eff ect of flavonoids on NFB activation was determined y using a sta le NFB luciferas e reporter cell line. Molecular doc ing simulations were performed to predict th e inding 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 wea inhi itors of BACE-1 activit y. Doc ing simulation studies with different BACE-1 structures also suggest that flavonoids are poor BACE-1 inhi itors as they appear to adopt various doc ing p oses in the active site poc et and have wea doc ing scores that differ as a fun ction of the BACE-1 structures studied. Moreover, a wea correlation was o serve d etween the effect of flavonoids on A production in vitro and their a ility to lower BACE-1 activity suggesting that the A lowering properties of flavonoids in whole cells are not mediated via direct inhi ition of BACE-1 activity. We found however a strong correlation etween the inhi ition of NFB activation y flavonoi ds and their A lowering properties suggesting that flavonoids inhi it A production in whole cells via NFB related mechanisms. As NFB has een shown to regulate BACE -1 expression, we show that NFB lowering flavonoids inhi it BACE-1 transcription in human neuronal SH-SY5Y cells. Altogether, our data suggest that flavonoids in hi it A and sAPP production y regulating BACE-1 expression and not y directly in hi iting BACE-1 activity. for more information on the Ros amp Institute and Alzheimers please visit: http://www.mullanalzheimer.com http://www.mullanalzheimer.info http://www.michaelmullan.us www.rfdn.org