International Journal of Alzheimer’s Disease

Y-Secretase Pharmacology: What Pharmacology Will Work for Alzheimer’s Disease?

Publishing date
21 Dec 2012
Submission deadline
03 Aug 2012

Lead Editor

1Neuroscience Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06392, USA

2Cellzome, Cambridge, UK

3Neural Pathways Discovery, GlaxoSmithKline, Singapore Research Center, Singapore

4Department of Neuropathology and Neuroscience, University of Tokyo, Tokyo, Japan

5Chiesi Farmaceutici, Parma, Italy

Y-Secretase Pharmacology: What Pharmacology Will Work for Alzheimer’s Disease?


Despite nearly two decades of sustained and widespread effort, the amyloid hypothesis of Alzheimer's disease (AD) remains to be rigorously tested in the clinic. Equivocal outcomes in recent clinical trials involving amyloid-directed approaches have naturally led to critical questions. Was it the amyloid hypothesis, the pharmacological target, the clinical experimental design, or the compounds that fell short? Two late-stage compounds targeting γ-secretase (flurbiprofen and LY-450139) were unsuccessful in phase III. However, given the lack of evidence for pharmacodynamic effect, the amyloid hypothesis was not rigorously tested by these two compounds. Thus, robust target engagement remains the main challenge for γ-secretase. The opportunities may lie in the uniquely rich pharmacology of γ-secretase. Current evidence suggests two distinct γ-secretase inhibitor (GSI) binding sites, two distinct γ-secretase modulator (GSM) binding sites, and a separate docking site for substrate binding. Further pharmacological complexity has been reported based on selectivity for different forms of the γ-secretase enzyme, such as enzyme isoforms containing alternative subunits or auxiliary subunits. Furthermore, direct and selective targeting of substrate has been proposed as an additional approach to suppression of γ cleavage. γ-Secretase thus presents a wide range of opportunities that may be exploitable in future trials. The aim of this special issue is therefore to bring together studies that improve and extend our understanding of the pharmacology of γ-secretase in order to distribute the knowledge that may be necessary for success in the clinic.

We are particularly interested in soliciting original research articles for this special issue. Potential topics include, but are not limited to:

  • Inhibitors and modulators of γ-secretase activity
  • Approaches to γ-secretase that can avoid the side-effects of γ-secretase inhibition
  • Behavioural and cognitive effects of GSI and GSM in animal models of AD or wild type animals
  • Structural approaches to γ-secretase
  • Selective inhibition of γ-secretase substrates or γ-secretase consisting of alternate subunits
  • Biologics approaches for γ-secretase
  • Cell biology and biological functions of γ-secretase and γ-secretase cleavage
  • Assay and translatable methods for γ-secretase pharmacodynamics
  • Critical comparison of γ-secretase inhibition/modulation with alternative Aβ-lowering approaches

Before submission authors should carefully read over the journal's Author Guidelines, which are located at Prospective authors should submit an electronic copy of their complete manuscript through the journal Manuscript Tracking System at according to the following timetable:


  • Special Issue
  • - Volume 2013
  • - Article ID 849128
  • - Editorial

γ-Secretase Pharmacology: What Pharmacology Will Work for Alzheimer's Disease?

Jeremy H. Toyn | Adele Rowley | ... | Bruno P. Imbimbo
  • Special Issue
  • - Volume 2013
  • - Article ID 823528
  • - Research Article

In Vivo Characterization of a Novel -Secretase Inhibitor SCH 697466 in Rodents and Investigation of Strategies for Managing Notch-Related Side Effects

Lynn A. Hyde | Qi Zhang | ... | Eric M. Parker
  • Special Issue
  • - Volume 2012
  • - Article ID 591392
  • - Review Article

-Secretase-Dependent Proteolysis of Transmembrane Domain of Amyloid Precursor Protein: Successive Tri- and Tetrapeptide Release in Amyloid -Protein Production

Mako Takami | Satoru Funamoto
  • Special Issue
  • - Volume 2012
  • - Article ID 210756
  • - Research Article

Modulation of Gamma-Secretase for the Treatment of Alzheimer's Disease

Barbara Tate | Timothy D. McKee | ... | Brian S. Bronk
  • Special Issue
  • - Volume 2012
  • - Article ID 295207
  • - Research Article

-Secretase Modulators: Can We Combine Potency with Safety?

Harrie J. M. Gijsen | Marc Mercken
  • Special Issue
  • - Volume 2012
  • - Article ID 289412
  • - Research Article

Morphologic and Functional Effects of Gamma Secretase Inhibition on Splenic Marginal Zone B Cells

Maria Cristina de Vera Mudry | Franziska Regenass-Lechner | ... | Alexander Flohr
International Journal of Alzheimer’s Disease
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