TY - JOUR
T1 - Modulation of gamma-secretase for the treatment of alzheimer's disease
AU - Tate, Barbara
AU - McKee, Timothy D.
AU - Loureiro, Robyn M.B.
AU - Dumin, Jo Ann
AU - Xia, Weiming
AU - Pojasek, Kevin
AU - Austin, Wesley F.
AU - Fuller, Nathan O.
AU - Hubbs, Jed L.
AU - Shen, Ruichao
AU - Jonker, Jeff
AU - Ives, Jeff
AU - Bronk, Brian S.
PY - 2012
Y1 - 2012
N2 - 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 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 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.
AB - 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 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 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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U2 - 10.1155/2012/210756
DO - 10.1155/2012/210756
M3 - Article
C2 - 23320246
AN - SCOPUS:84872139600
SN - 2090-0252
JO - International Journal of Alzheimer's Disease
JF - International Journal of Alzheimer's Disease
M1 - 210756
ER -