The β- and γ-secretases responsible for the formation of the amyloid β-peptide (Aβ) have been top targets for the development of Alzheimer therapeutics even before the identification of these proteases. Indeed, secretase inhibitors have been sought ever since the discovery of AD-causing missense mutations in APP [1-3] and the realization that these mutations alter Aβ production [4-6]. Cell-based screens netted a number of compounds that blocked Aβ formation, and virtually all of these initial leads appeared to work at the level of γ-secretase [7-11]. The identification of β- and γ-secretases ultimately revealed why this was the case. β-Secretase is a membrane-tethered pepsin-like aspartyl protease [12-15] that cleaves APP on the lumenal/extracellular side at the juxtamembrane region. The enzyme has a long and shallow active site , and molecules that inhibit β-secretase are typically not very cell permeable. In contrast, γ-secretase cleaves within the transmembrane region of APP and contains a membrane-embedded active site . Thus, compounds that inhibit γ-secretase are typically quite hydrophobic and readily traverse the cell membrane. For these reasons, γ-secretase inhibitors have advanced further along the drug development pipeline than β-secretase inhibitors, which are only just emerging from the preclinical stage.
γ-Secretase is nevertheless a difficult drug target in some other respects. In stark contrast to β-secretase, γ-secretase is a large protein complex composed of four different membrane proteins [18-20], and knowledge of structural details that would allow rational drug design is not available. Moreover, γ-secretase processes a number of different type I integral membrane proteins, so many that this protease has been dubbed “the proteasome of the membrane” . Many of these processing events are part of critical pathways in cell biology that may have toxic consequences if blocked. Indeed, this is already well known to be the case with one particular γ-secretase substrate, the Notch receptor. Thus, modulation rather than inhibition of γ-secretase is preferred, to alter Aβ production in a therapeutically relevant way without interfering with essential cellular processes. This minireview provides an overview of the various types of γ-secretase inhibitors and modulators and what is known about how they interact with the protease complex, their mechanisms of action, and their potential as disease-modifying therapies for AD.