Novel modulators of amyloid-β precursor protein processing

Abstract

Proteolytic processing of the amyloid precursor protein (APP) is modulated by the action of enzymes α-, β- and γ-secretases, with the latter two mediating the amyloidogenic production of amyloid-β (Aβ). Cellular modulators of APP processing are well known from studies of genetic mutations (such as those found in APP and presenilins) or polymorphisms (such as the apolipoprotein E4 ε-allele) that predisposes an individual to early or late-onset Alzheimer's disease. In recent years, several classes of molecule with modulating functions in APP processing and Aβ secretion have emerged. These include the neuronal Munc-18 interacting proteins (Mints)/X11s, members of the reticulon family (RTN-3 and RTN-4/Nogo-B), the Nogo-66 receptor (NgR), the peptidyl-prolyl isomerase Pin1 and the Rho family GTPases and their effectors. Mints and NgR bind to APP directly, while RTN3 and Nogo-B interact with the β-secretase BACE1. Phosphorylated APP is a Pin1 substrate, which binds to its phosphor-Thr668-Pro motif. These interactions by and large resulted in a reduction of Aβ generation both in vitro and in vivo. Inhibition of Rho and Rho-kinase (ROCK) activity may underlie the ability of non-steroidal anti-inflammatory drugs and statins to reduce Aβ production, a feat which could also be achieved by Rac1 inhibition. Detailed understanding of the underlying mechanisms of action of these novel modulators of APP processing, as well as insights into the molecular neurological basis of how Aβ impairs leaning and memory, will open up multiple avenues for the therapeutic intervention of Alzheimer's disease. © 2007 The Authors.