title: Targets for AD treatment: conflicting messages from γ-secretase inhibitors.
abstract: Current evidence suggests that Alzheimer's disease (AD) is a multi-factorial disease that starts with accumulation of multiple proteins. We have previously proposed that inhibition of γ-secretase may impair membrane recycling causing neurodegeneration starting at synapses (Sambamurti K., Suram A., Venugopal C., Prakasam A., Zhou Y., Lahiri D. K. and Greig N. H. A partial failure of membrane protein turnover may cause Alzheimer's disease: a new hypothesis. Curr. Alzheimer Res., 3, 2006, 81). We also proposed familal AD mutations increase Aβ42 by inhibiting γ-secretase. Herein, we discuss the failure of Eli Lilly's γ-secretase inhibitor, semagacestat, in clinical trials in the light of our hypothesis, which extends the problem beyond toxicity of Aβ aggregates. We elaborate that γ-secretase inhibitors lead to accumulation of amyloid precursor protein C-terminal fragments that can later be processed by γ-secretase to yields bursts of Aβ to facilitate aggregation. Although we do not exclude a role for toxic Aβ aggregates, inhibition of γ-secretase can affect numerous substrates other than amyloid precursor protein to affect multiple pathways and the combined accumulation of multiple peptides in the membrane may impair its function and turnover. Taken together, protein processing and turnover pathways play an important role in maintaining cellular homeostasis and unless we clearly see consistent disease-related increase in their levels or activity, we need to focus on preserving their function rather than inhibiting them for treatment of AD and similar diseases.
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425, USA. sambak@musc.edu
authors.forename: Kumar
authors.initials: K
authors.lastname: Sambamurti
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
authors.forename: Tadanobu
authors.initials: T
authors.lastname: Utsuki
authors.forename: Eliza L
authors.initials: EL
authors.lastname: Barnwell
authors.forename: Ekta
authors.initials: E
authors.lastname: Sharma
authors.forename: Cheryl
authors.initials: C
authors.lastname: Mazell
authors.forename: Narayan R
authors.initials: NR
authors.lastname: Bhat
authors.forename: Mark S
authors.initials: MS
authors.lastname: Kindy
authors.forename: Debomoy K
authors.initials: DK
authors.lastname: Lahiri
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Pappolla
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans
chemical_list: D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases