Effects of peptides derived from BACE1 catalytic domain on APP processing

One of the hallmarks of Alzheimer's disease (AD) is the deposition of β-amyloid (Aβ) peptides in neuritic plaques. Aβ peptides are derived from sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases. β-APP cleaving enzyme-1 (BACE1) has been shown to be the major β-secretase and is a primary therapeutic target for AD. We report here novel BACE1 inhibitory peptidomimetics, which are derived from catalytic domains of BACE1 themselves, instead of APP cleavage sites and are structurally modified by myristoylation in N-terminus for efficient cell permeability. The peptides not only inhibited the formation of APPβ (a soluble N-terminal fragment of APP cleaved by β-secretase), but also significantly reduced Aβ40 production. Our results suggest a new approach for identifying inhibitory agents for the treatment of AD.