Rinsho Shinkeigaku (Clinical Neurology)

The 49th Annual Meeting of the Japanese Society of Neurology

Targeting the structure and function relationships of the γ-secretase for the development of Alzheimer's disease

Taisuke Tomita, M.D.

Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo

Genetic and biological studies provide evidence that the production and deposition of amyloid-β peptides (Aβ) contribute to the etiology of Alzheimer's disease. Thus, β- and γ-secretases, that are involved in the Aβ generation, 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 AD, although recent studies suggest that γ-secretase plays important roles in cellular signaling including Notch pathway. 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. I will review our structural studies on the γ-secretase complex, and envision the direction for developing effective and selective γ-secretase inhibitors as therapeutics for AD.
Full Text of this Article in Japanese PDF (418K)

(CLINICA NEUROL, 48: 907|909, 2008)
key words: Alzheimer's disease, amyloid β protein, amyloid β protein precursor, γ-secretase inhibitor, γ-secretase modulator

(Received: 16-May-08)