Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease

Abstract

Accumulation of neurotoxic amyloid-β is a major hallmark of Alzheimer's disease1. Formation of amyloid-β is catalysed by γ-secretase, a protease with numerous substrates2,3. Little is known about the molecular mechanisms that confer substrate specificity on this potentially promiscuous enzyme. Knowledge of the mechanisms underlying its selectivity is critical for the development of clinically effective γ-secretase inhibitors that can reduce amyloid-β formationwithout impairingcleavage of other γ-secretase substrates, especiallyNotch, which is essential for normal biological functions3,4. Here we report the discovery of a novel γ-secretase activating protein (GSAP) that drastically and selectively increases amyloid-β production through a mechanism involving its interactions with both γ-secretase and its substrate, the amyloid precursor protein carboxy-terminal fragment (APP-CTF). GSAP does not interact with Notch, nor does it affect its cleavage. Recombinant GSAP stimulates amyloid-β production in vitro. Reducing GSAP concentrations in cell lines decreases amyloid-β concentrations. Knockdown of GSAP in a mouse model of Alzheimer's disease reduces levels of amyloid-β and plaque development. GSAP represents a type of γ-secretase regulator that directs enzyme specificity by interacting with a specific substrate.We demonstrate that imatinib, an anticancer drug previously found to inhibit amyloid-β formation without affecting Notch cleavage5, achieves its amyloid-β-lowering effect by preventing GSAP interactionwith the γ-secretase substrate, APP-CTF. Thus, GSAP can serve as an amyloid-β-lowering therapeutic target without affecting other key functions of γ-secretase. © 2010 Macmillan Publishers Limited. All rights reserved.