title: Modulation of gamma-secretase for the treatment of Alzheimer's disease.
abstract: 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.
authors: Satori Pharmaceuticals, Inc., 281 Albany Street, Cambridge, MA 02139, USA.
authors: Barbara
authors: B
authors: Tate
authors: Timothy D
authors: TD
authors: McKee
authors: Robyn M B
authors: RM
authors: Loureiro
authors: Jo Ann
authors: JA
authors: Dumin
authors: Weiming
authors: W
authors: Xia
authors: Kevin
authors: K
authors: Pojasek
authors: Wesley F
authors: WF
authors: Austin
authors: Nathan O
authors: NO
authors: Fuller
authors: Jed L
authors: JL
authors: Hubbs
authors: Ruichao
authors: R
authors: Shen
authors: Jeff
authors: J
authors: Jonker
authors: Jeff
authors: J
authors: Ives
authors: Brian S
authors: BS
authors: Bronk