The Amyloid Hypothesis states that the cascade of events associated with Alzheimer's disease (AD)—formation of amyloid plaques, neurofibrillary tangles, synaptic loss, neurodegeneration, and cognitive decline—are triggered by Aβ peptide dysregulation (Kakuda et al., 2006, Sato et al., 2003, Qi-Takahara et al., 2005). Since γ-secretase is critical for Aβ production, many in the biopharmaceutical community focused on γ-secretase as a target for therapeutic approaches for Alzheimer's disease. However, pharmacological approaches to control γ-secretase activity are challenging because the enzyme has multiple, physiologically critical protein substrates. To lower amyloidogenic Aβ peptides without affecting other γ-secretase substrates, the epsilon (ε) cleavage that is essential for the activity of many substrates must be preserved. Small molecule modulators of γ-secretase activity have been discovered that spare the ε cleavage of APP and other substrates while decreasing the production of Aβ42. Multiple chemical classes of γ-secretase modulators have been identified which differ in the pattern of Aβ peptides produced. Ideally, modulators will allow the ε cleavage of all substrates while shifting APP cleavage from Aβ42 and other highly amyloidogenic Aβ peptides to shorter and less neurotoxic forms of the peptides without altering the total Aβ pool. Here, we compare chemically distinct modulators for effects on APP processing and in vivo activity. 1. Introduction Gamma-secretase (γ-secretase) is required for the production of amyloid beta peptides (Aβ) and decreasing Aβ production as a disease modifying approach for the treatment of Alzheimer’s disease (AD) has received intense interest. The initial focus was on the discovery of compounds that would decrease γ-secretase activity. γ-Secretase cleaves the membrane bound C-terminal domain (C99) of APP at the site to produce the intracellular domain, AICD. The enzyme then makes sequential cuts of the remaining intramembrane APP fragment at each turn of the alpha helix (every 3-4 amino acids) until Aβ peptides are formed and released into the extracellular space [1–3]. This protein processivity produces Aβ peptides that vary in size, from 43–34 amino acids in length [4, 5]. In Alzheimer’s disease, a greater number of the longer forms of Aβ, including Aβ42 and Aβ43, or a high ratio of the long peptides to the shorter forms, appear to occur [6]. These longer Aβ peptides readily oligomerize, forming toxic species, as well as becoming the seeds for amyloid plaques [7, 8]. The full inhibition of γ-secretase appeared to
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