Hindawi Publishing Corporation International Journal of Alzheimer’s Disease Volume 2012, Article ID 210756, 10 pages doi:10.1155/2012/210756 Research Article Modulation of Gamma-Secretase for the Treatment of Alzheimer’s Disease Barbara Tate, Timothy D. McKee, Robyn M. B. Loureiro, Jo Ann Dumin, Weiming Xia, Kevin Pojasek, Wesley F. Austin, Nathan O. Fuller, Jed L. Hubbs, Ruichao Shen, Jeff Jonker, Jeff Ives, and Brian S. Bronk Satori Pharmaceuticals, Inc., 281 Albany Street, Cambridge, MA 02139, USA Correspondence should be addressed to Barbara Tate, barbara.tate@satoripharma.com Received 13 August 2012; Accepted 8 November 2012 Academic Editor: Jeremy Toyn Copyright © 2012 Barbara Tate et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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 Aβ 42 . 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 Aβ 42 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 pro- duction 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 ε 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 Aβ 42 and Aβ 43 , 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 be a sound approach. However, it was found that γ-secretase plays a broader biological role and cleaves multiple proteins to yield physiologically essential products. Thus, total inhibition results in severe adverse effects in vivo [9–11]. This played out in the clinic in the trial of the γ-secretase inhibitor, semagacestat from Eli Lilly [12–14]. Patients treated with this drug developed skin and gastrointestinal side effects that are characteristic of the inhibition of γ-secretase processing of Notch, leading to the discontinuation of the clinical trial in 2010 [13, 14]. The discovery of compounds that could decrease the production of the more amyloidogenic Aβ 42 peptide while preserving total Aβ levels and γ-secretase cleavage of other substrates led to a clinical trial of one of these newly