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

Abstract

Much of the work on potential anti-Alzheimer's disease drugs has been focused on compounds that reduce the accumulation of neurotoxic amyloid-β peptide in the brain. This has met with little success, in part because agents that block γ-secretase also block processing of Notch, a signalling protein essential for many homeostatic functions, resulting in severe side effects. Now the discovery of a γ-secretase activating protein (GSAP) that selectively controls amyloid-β generation without influencing Notch cleavage suggests a possible new target for anti-Alzheimer's drugs. The anticancer drug imatinib (Gleevec), known to inhibit amyloid-β formation without affecting Notch cleavage, is shown to act via an effect on GSAP. This suggests that GSAP inhibitors that can cross the blood–brain barrier (unlike imatinib) may hold promise for treating Alzheimer's disease. A major hallmark of Alzheimer's disease is the accumulation in the brain of amyloid-β peptide. This is generated by γ-secretase, which is thus of interest as a target for drugs to prevent amyloid-β accumulation. A problem is that γ-secretase has other substrates, including Notch, important in development. Here, a γ-secretase activating protein is identified that increases amyloid-β production without affecting Notch. Thus this protein can serve as an amyloid-β-lowering drug target without affecting other functions of γ-secretase. 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 formation without impairing cleavage of other γ-secretase substrates, especially Notch, 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 interaction with 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.