Despite nearly two decades of sustained and widespread effort, the amyloid hypothesis of Alzheimer's disease (AD) remains to be rigorously tested in the clinic. Equivocal outcomes in recent clinical trials involving amyloid-directed approaches have naturally led to critical questions. Was it the amyloid hypothesis, the pharmacological target, the clinical experimental design, or the compounds that fell short? Two late-stage compounds targeting γ-secretase (flurbiprofen and LY-450139) were unsuccessful in phase III. However, given the lack of evidence for pharmacodynamic effect, the amyloid hypothesis was not rigorously tested by these two compounds. Thus, robust target engagement remains the main challenge for γ-secretase. The opportunities may lie in the uniquely rich pharmacology of γ-secretase. Current evidence suggests two distinct γ-secretase inhibitor (GSI) binding sites, two distinct γ-secretase modulator (GSM) binding sites, and a separate docking site for substrate binding. Further pharmacological complexity has been reported based on selectivity for different forms of the γ-secretase enzyme, such as enzyme isoforms containing alternative subunits or auxiliary subunits. Furthermore, direct and selective targeting of substrate has been proposed as an additional approach to suppression of γ cleavage. γ-Secretase thus presents a wide range of opportunities that may be exploitable in future trials. The aim of this special issue is therefore to bring together studies that improve and extend our understanding of the pharmacology of γ-secretase in order to distribute the knowledge that may be necessary for success in the clinic.

We are particularly interested in soliciting original research articles for this special issue. Potential topics include, but are not limited to:

• Inhibitors and modulators of γ-secretase activity
• Approaches to γ-secretase that can avoid the side-effects of γ-secretase inhibition
• Behavioural and cognitive effects of GSI and GSM in animal models of AD or wild type animals
• Structural approaches to γ-secretase
• Selective inhibition of γ-secretase substrates or γ-secretase consisting of alternate subunits
• Biologics approaches for γ-secretase
• Cell biology and biological functions of γ-secretase and γ-secretase cleavage
• Assay and translatable methods for γ-secretase pharmacodynamics
• Critical comparison of γ-secretase inhibition/modulation with alternative Aβ-lowering approaches

Before submission authors should carefully read over the journal's Author Guidelines, which are located at http://www.hindawi.com/journals/ijad/guidelines/. Prospective authors should submit an electronic copy of their complete manuscript through the journal Manuscript Tracking System at http://mts.hindawi.com/ according to the following timetable: