Targets for AD treatment: Conflicting messages from γ-secretase inhibitors

Kumar Sambamurti, Nigel H. Greig, Tadanobu Utsuki, Eliza L. Barnwell, Ekta Sharma, Cheryl Mazell, Narayan R. Bhat, Mark S. Kindy, Debomoy K. Lahiri, Miguel A. Pappolla

Research output: Contribution to journalReview articlepeer-review

69 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)359-374
Number of pages16
JournalJournal of neurochemistry
Issue number3
StatePublished - May 2011
Externally publishedYes


  • Alzheimer
  • amyloid
  • degeneration
  • gamma-secretase.

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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