%0 Journal Article
%T Modulation of Gamma-Secretase for the Treatment of Alzheimer's Disease
%A Barbara Tate
%A Timothy D. McKee
%A Robyn M. B. Loureiro
%A Jo Ann Dumin
%A Weiming Xia
%A Kevin Pojasek
%A Wesley F. Austin
%A Nathan O. Fuller
%A Jed L. Hubbs
%A Ruichao Shen
%A Jeff Jonker
%A Jeff Ives
%A Brian S. Bronk
%J International Journal of Alzheimer's Disease
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/210756
%X The Amyloid Hypothesis states that the cascade of events associated with Alzheimer's disease (AD)¡ªformation of amyloid plaques, neurofibrillary tangles, synaptic loss, neurodegeneration, and cognitive decline¡ªare triggered by A¦Â peptide dysregulation (Kakuda et al., 2006, Sato et al., 2003, Qi-Takahara et al., 2005). Since ¦Ã-secretase is critical for A¦Â production, many in the biopharmaceutical community focused on ¦Ã-secretase as a target for therapeutic approaches for Alzheimer's disease. However, pharmacological approaches to control ¦Ã-secretase activity are challenging because the enzyme has multiple, physiologically critical protein substrates. To lower amyloidogenic A¦Â peptides without affecting other ¦Ã-secretase substrates, the epsilon (¦Å) cleavage that is essential for the activity of many substrates must be preserved. Small molecule modulators of ¦Ã-secretase activity have been discovered that spare the ¦Å cleavage of APP and other substrates while decreasing the production of A¦Â42. Multiple chemical classes of ¦Ã-secretase modulators have been identified which differ in the pattern of A¦Â peptides produced. Ideally, modulators will allow the ¦Å cleavage of all substrates while shifting APP cleavage from A¦Â42 and other highly amyloidogenic A¦Â peptides to shorter and less neurotoxic forms of the peptides without altering the total A¦Â pool. Here, we compare chemically distinct modulators for effects on APP processing and in vivo activity. 1. Introduction Gamma-secretase (¦Ã-secretase) is required for the production of amyloid beta peptides (A¦Â) and decreasing A¦Â 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 ¦Ã-secretase activity. ¦Ã-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 A¦Â peptides are formed and released into the extracellular space [1¨C3]. This protein processivity produces A¦Â peptides that vary in size, from 43¨C34 amino acids in length [4, 5]. In Alzheimer¡¯s disease, a greater number of the longer forms of A¦Â, including A¦Â42 and A¦Â43, or a high ratio of the long peptides to the shorter forms, appear to occur [6]. These longer A¦Â peptides readily oligomerize, forming toxic species, as well as becoming the seeds for amyloid plaques [7, 8]. The full inhibition of ¦Ã-secretase appeared to
%U http://www.hindawi.com/journals/ijad/2012/210756/