γ-Secretase Substrates and their Implications for Drug Development in Alzheimer's Disease

gamma-secretase is an aspartyl protease that cleaves a large number of substrates within the membrane environment. This multiprotein complex is responsible for the last cleavage step of the beta-amyloid precursor protein (APP) that generates the amyloid-beta peptide (A beta), one of the primary components of amyloid plaques in Alzheimer's disease (AD). Over the last years, more than 90 type-I membrane proteins have been shown to be cleaved by gamma-secretase. The mechanism and function of this cleavage event is not yet well understood. The gamma-secretase cleavage of some substrates releases intracellular domains with critical signaling properties. In contrast, the cleavage of other substrates seems to have a mere degradative function. Knowledge about gamma-secretase substrates and their function has clear implications for the development of new therapies for AD. Most gamma-secretase inhibitors interfere with the cleavage of the Notch receptor, which is known to lead to adverse effects in animal models and in humans. Paradoxically, due to this effect, gamma-secretase inhibitors are actively being investigated in cancer. An alternative approach is modulation of gamma-secretase, in which small molecules allosterically attenuate the activity to reduce A beta(42), the most fibrillogenic species. Although tolerance and efficacy of some gamma-secretase inhibitors in AD have shown to be poor in clinical trials, more selective compounds are on the road. As these compounds advance to clinical trials it is critical to understand the mechanism by which gamma-secretase recognizes and cleaves this diverse set of substrates to predict possible adverse effects in humans. This knowledge will help to guide drug development in AD and cancer.