Inhibitory effects of key compounds isolated from Corni fructus on BACE1 Activity.

Progressive cerebral deposition of Aβ in the brain is a seminal event in the pathogenesis of Alzheimer's disease (AD). Aβ is generated from the amyloid precursor protein (APP) by proteolytic processing of β-secretase (BACE1) and γ-secretase. Consequently, BACE1, a key enzyme in the production of Aβ, is a prime target for therapeutic intervention in AD. In the course of screening for natural BACE1 inhibitors from Corni fructus, the ethyl acetate (EtOAc) fraction showed significant inhibitory activity against BACE1. By activity guided purification, three compounds of BACE1 inhibitors p-coumaric acid, gallic acid and ursolic acid were isolated from Corni fructus EtOAc fraction. All isolated compounds suppressed BACE1 in a dose dependent manner. p-Coumaric acid, in particular, exhibited significant inhibitory activity against BACE1 with 9.0 × 10(-5)  m and a K(i) value of 1.9 × 10(-6)  m. Also this compound was non-competitive with a substrate in the Dixon plot, suggesting that it might bind either to the β-secretase subsite or to another regulatory site. All compounds showed no significant attenuation of TACE (α-secretase) and other serine proteases such as chymotrypsin and trypsin, demonstrating that they were relatively selective and specific inhibitors of BACE1. These novel findings suggest that Corni fructus contains biologically active components that may be used to attenuate the progression and/or prevention of Alzheimer's disease.