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Inhibition of γ-Secretase as a Therapeutic Intervention for Alzheimer’s Disease

Prospects, Limitations and Strategies

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Abstract

Genetic and experimental evidence points to amyloid-β (Aβ) peptide as the culprit in Alzheimer’s disease pathogenesis. This protein fragment abnormally accumulates in the brain cortex and hippocampus of patients with Alzheimer’s disease, and self-aggregates to form toxic oligomers causing neurodegeneration.

Aβ is heterogeneous and produced from a precursor protein (amyloid precursor protein [APP]) by two sequential proteolytic cleavages that involve β- and γ-secretases. This latter enzyme represents a potentially attractive drug target since it dictates the solubility of the generated Aβ fragment by creating peptides of various lengths, namely Aβ40 and Aβ42, the longest being the most aggregating. γ-Secretase comprises a molecular complex of four integral membrane proteins — presenilin,nicastrin, APH-1 and PEN-2 — and its molecular mechanism remains under extensive scrutiny. The ratio of Aβ42 over Aβ40 is increased by familial Alzheimer’s disease mutations occurring in the presenilin genes or in APP, near the γ-secretase cleavage site.

Potent γ-secretase inhibitors have been identified by screening drug libraries or by designing aspartyl protease transition-state analogues based on the APP substrate cleavage site. Most of these compounds are not specific for γ-secretase cleavage of APP, and equally inhibit the processing of other γ-secretase substrates, such as Notch and a subset of cell-surface receptors and proteins involved in embryonic development, haematopoiesis, cell adhesion and cell/cell contacts. Therefore, current research aims at finding compounds that show selectivity for APP cleavage, and particularly that inhibit the formation of the aggregating form, Aβy42. Compounds that target the substrate docking site rather than the enzyme active site are also being investigated as an alternative strategy. The finding that some NSAID analogues preferentially inhibit the formation of Aβ42 over Aβ40 and do not affect Notch processing has opened a new therapeutic window. The progress in design of selective inhibitors as well as recent results obtained in animal studies prove that γ-secretase remains among the best targets for the therapeutic control of amyloid build-up in Alzheimer’s disease. The full understanding of γ-secretase regulation may yet uncover new therapeutic leads.

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Acknowledgements

Geneviève Evin and Colin L. Masters are supported by the National Health and Medical Research Council (Australia), grants 114150 and 400073. Colin L. Masters is Executive Director and Chairman of the Scientific Advisory Board of Prana Biotechnology Ltd, a company aimed at providing therapeutic intervention for age-related disease. All authors declare they have no conflicts of interest that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Department of Pathology, The University of Melbourne, Parkville, Victoria, 3010, Australia

    Geneviève Evin, Marijke Fleur Sernee & Colin L. Masters

  2. The Mental Health Research Institute, Parkville, Victoria, Australia

    Geneviève Evin, Marijke Fleur Sernee & Colin L. Masters

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  1. Geneviève Evin
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  2. Marijke Fleur Sernee
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  3. Colin L. Masters
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Correspondence to Geneviève Evin.

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Evin, G., Sernee, M.F. & Masters, C.L. Inhibition of γ-Secretase as a Therapeutic Intervention for Alzheimer’s Disease. CNS Drugs 20, 351–372 (2006). https://doi.org/10.2165/00023210-200620050-00002

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