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 Pappolla

Research output: Contribution to journalArticle

60 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)359-374
Number of pages16
JournalJournal of Neurochemistry
Volume117
Issue number3
DOIs
StatePublished - May 2011
Externally publishedYes

Fingerprint

Amyloid Precursor Protein Secretases
Alzheimer Disease
N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide
Membranes
Amyloid beta-Protein Precursor
Poisons
Protein C
Amyloid
Synapses
Membrane Proteins
Proteins
Homeostasis
Toxicity
Recycling
Clinical Trials
Agglomeration
Peptides
Mutation
Substrates
Processing

Keywords

  • Alzheimer
  • amyloid
  • degeneration
  • gamma-secretase.

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Sambamurti, K., Greig, N. H., Utsuki, T., Barnwell, E. L., Sharma, E., Mazell, C., ... Pappolla, M. (2011). Targets for AD treatment: Conflicting messages from γ-secretase inhibitors. Journal of Neurochemistry, 117(3), 359-374. https://doi.org/10.1111/j.1471-4159.2011.07213.x

Targets for AD treatment : Conflicting messages from γ-secretase inhibitors. / Sambamurti, Kumar; Greig, Nigel H.; Utsuki, Tadanobu; Barnwell, Eliza L.; Sharma, Ekta; Mazell, Cheryl; Bhat, Narayan R.; Kindy, Mark S.; Lahiri, Debomoy K.; Pappolla, Miguel.

In: Journal of Neurochemistry, Vol. 117, No. 3, 05.2011, p. 359-374.

Research output: Contribution to journalArticle

Sambamurti, K, Greig, NH, Utsuki, T, Barnwell, EL, Sharma, E, Mazell, C, Bhat, NR, Kindy, MS, Lahiri, DK & Pappolla, M 2011, 'Targets for AD treatment: Conflicting messages from γ-secretase inhibitors', Journal of Neurochemistry, vol. 117, no. 3, pp. 359-374. https://doi.org/10.1111/j.1471-4159.2011.07213.x
Sambamurti K, Greig NH, Utsuki T, Barnwell EL, Sharma E, Mazell C et al. Targets for AD treatment: Conflicting messages from γ-secretase inhibitors. Journal of Neurochemistry. 2011 May;117(3):359-374. https://doi.org/10.1111/j.1471-4159.2011.07213.x
Sambamurti, Kumar ; Greig, Nigel H. ; Utsuki, Tadanobu ; Barnwell, Eliza L. ; Sharma, Ekta ; Mazell, Cheryl ; Bhat, Narayan R. ; Kindy, Mark S. ; Lahiri, Debomoy K. ; Pappolla, Miguel. / Targets for AD treatment : Conflicting messages from γ-secretase inhibitors. In: Journal of Neurochemistry. 2011 ; Vol. 117, No. 3. pp. 359-374.
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