Degradation of gamma secretase activating protein by the ubiquitin-proteasome pathway

A major hallmark feature of Alzheimer's disease is the accumulation of amyloid beta (A beta), whose formation is regulated by the -secretase complex and its activating protein (also known as gamma-secretase activating protein, or GSAP). Because GSAP interacts with the gamma-secretase without affecting the cleavage of Notch, it is an ideal target for a viable anti-A beta therapy. GSAP derives from a C-terminal fragment of a larger precursor protein of 98kDa via a caspase 3-mediated cleavage. However, the mechanism(s) involved in its degradation remain unknown. In this study, we show that GSAP has a short half-life of approximately 5h. Neuronal cells treated with proteasome inhibitors markedly prevented GSAP protein degradation, which was associated with a significant increment in A beta levels and gamma-secretase cleavage products. In contrast, treatment with calpain blocker and lysosome inhibitors had no effect. In addition, we provide experimental evidence that GSAP is ubiquitinated. Taken together, our findings reveal that GSAP is degraded through the ubiquitin-proteasome system. Modulation of the GSAP degradation pathway may be implemented as a viable target for a safer anti-A beta therapeutic approach in Alzheimer's disease.