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CNS Drugs

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01.05.2006 | Leading Article

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

Prospects, Limitations and Strategies

verfasst von: Dr Geneviève Evin, Marijke Fleur Sernee, Colin L. Masters

Erschienen in: CNS Drugs | Ausgabe 5/2006

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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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Titel: Inhibition of γ-Secretase as a Therapeutic Intervention for Alzheimer’s Disease
Prospects, Limitations and Strategies
verfasst von: Dr Geneviève Evin
Marijke Fleur Sernee
Colin L. Masters
Publikationsdatum: 01.05.2006
Verlag: Springer International Publishing
Erschienen in: CNS Drugs / Ausgabe 5/2006
Print ISSN: 1172-7047
Elektronische ISSN: 1179-1934
DOI: https://doi.org/10.2165/00023210-200620050-00002

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