Gamma Secretase-Activating Protein Is a Substrate for Caspase-3: Implications for Alzheimer's Disease

BACKGROUND: A major feature of Alzheimer's disease (AD) is the accumulation of amyloid-beta (A beta), whose formation is regulated by the gamma-secretase complex and its activating protein (also known as GSAP). Because GSAP interacts with gamma-secretase without affecting the cleavage of Notch, it is an ideal target for a viable anti-A beta therapy. However, despite much interest in this protein, the mechanisms involved in its neurobiology are unknown. METHODS: Postmortem brain tissue samples from AD patients, transgenic mouse models of AD, and neuronal cells were used to investigate the molecular mechanism involved in GSAP formation and subsequent amyloidogenesis. RESULTS: We identified a caspase-3 processing domain in the GSAP sequence and provide experimental evidence that this caspase is essential for GSAP activation and biogenesis of A beta peptides. Furthermore, we demonstrated that caspase-3-dependent GSAP formation occurs in brains of individuals with AD and two different mouse models of AD and that the process is biologically relevant because its pharmacological blockade reduces A beta pathology in vivo. CONCLUSIONS: Our data, by identifying caspase-3 as the endogenous modulator of GSAP and A beta production, establish caspase-3 as a novel, attractive and viable A beta-lowering therapeutic target for AD.