Modulation of gamma-secretase for the treatment of Alzheimer's disease.

Tate B, McKee TD, Loureiro RM, Dumin JA, Xia W, Pojasek K, Austin WF, Fuller NO, Hubbs JL, Shen R, Jonker J, Ives J, Bronk BS.
Journal   Int J Alzheimers Dis.
Species  
Analytes Measured   Abeta 38 , Abeta 40 , Abeta 42
Matrix Tested   Cell culture medium, brain homogenates
Year   2012
Volume   2012
Page Numbers   210756
Application   Alzheimers
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.

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