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Assembly and activation of the γ-secretase complex: roles of presenilin cofactors

Molecular Psychiatry volume 9, pages 8–10 (2004)Cite this article

A small percentage of patients with Alzheimer's disease (AD) inherit the illness as an early onset familial autosomal-dominant trait. Molecular genetic analysis of pedigrees of early-onset familial AD (FAD) revealed three different pathogenic genes, that is, those coding for β-amyloid precursor protein (APP), presenilin 1 (PS1) and PS2. Subsequent studies using transfected cells and transgenic mice showed that most of the pathogenic mutations of these genes led to overproduction of amyloid β peptides (Aβ) ending at 42nd amino-acid residue (Aβ42).1,2 Aβ42 is the Aβ species that most readily forms amyloid in vitro, and which is initially deposited as senile plaques in AD brains3, implicating Aβ in the pathogenesis of AD.

γ-Secretase is a unique membrane-bound protease responsible for the intramembrane cleavage of a subset of type I membrane-spanning proteins including APP and Notch. The cleavage occurs after ectodomain shedding of the target protein. γ-Secretase plays a seminal role in the pathogenesis of AD by generating the C terminus of Aβ, including the more amyloidogenic Aβ42 peptide. The following lines of evidence suggested that presenilin (PS) was closely related to the activity of γ-secretase: (1) FAD-linked mutations of PS shifted the preferred site of γ-cleavage from position 40 to 42 of Aβ2; (2) γ-secretase activity was diminished in cells derived from PS knockout mice4; (3) substitution of either of the two Asp residues buried within the 6th and 7th transmembrane domains of PS abolished γ-secretase activity.5

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Acknowledgements

We thanks Drs Michael C Irizarry and Taisuke Tomita for valuable comments on the manuscript.

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

    Takeshi Iwatsubo

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  1. Takeshi Iwatsubo
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Correspondence to Takeshi Iwatsubo.

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Iwatsubo, T. Assembly and activation of the γ-secretase complex: roles of presenilin cofactors. Mol Psychiatry 9, 8–10 (2004). https://doi.org/10.1038/sj.mp.4001438

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