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At the frontline of Alzheimer’s disease treatment: γ-secretase inhibitor/modulator mechanism

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Abstract

Genetic and biological studies provide evidence that the production and deposition of amyloid-β peptides (Aβ) contribute to the etiology of Alzheimer’s disease. β- and γ-secretases, which are responsible for the generation of Aβ, are plausible molecular targets for Alzheimer’s disease treatment. γ-Secretase is an unusual aspartic protease that cleaves the scissile bond within the transmembrane domain. This unusual enzyme is composed of a high molecular weight membrane protein complex containing presenilin, nicastrin, Aph-1 and Pen-2. Drugs that regulate the production of Aβ by inhibiting or modulating γ-secretase activity could provide a disease-modifying effect on Alzheimer’s disease, although recent studies suggest that γ-secretase plays important roles in cellular signaling including Notch. Thus, understanding the molecular mechanism whereby γ-secretase recognizes and cleaves its substrate is a critical issue for the development of compounds that specifically regulate Aβ-generating γ-secretase activity. This review focuses on the structure and function relationship of γ-secretase complex and the mode of action of the γ-secretase inhibitors.

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Acknowledgments

I am grateful to Dr. Takeshi Iwatsubo (The University of Tokyo) and all colleagues who collaborated in the studies cited in this review.

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  1. Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Taisuke Tomita

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  1. Taisuke Tomita
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Correspondence to Taisuke Tomita.

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Tomita, T. At the frontline of Alzheimer’s disease treatment: γ-secretase inhibitor/modulator mechanism. Naunyn-Schmied Arch Pharmacol 377, 295–300 (2008). https://doi.org/10.1007/s00210-007-0206-2

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