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Alzheimer's disease

In search of γ-secretase

Nature volume 398, pages 466–467 (1999)Cite this article

When the race was on to identify the genes on chromosomes 14 and 1 which, when they contain mutations, lead to early-onset Alzheimer's disease, it was generally thought that they would encode enzymes involved in the processing of the β-amyloid precursor protein (APP). It is a derivative of APP, the neurotoxic peptide Aβ, that is implicated as the main agent of the disease. When candidate genes, called the presenilins, were cloned, their only known protein homologues were apparently involved in vesicle transport or the Notch developmental pathway in the nematode Caenorhabditis elegans. Subsequent work in transgenic mice and transfected cells, however, soon showed that mutations in presenilins all altered APP processing and caused increased levels of the 42-amino-acid β-amyloid derivative Aβ42. (See ref. 1 for references.)

Since then there has been intense interest in the relationship between Aβ production, the presenilins, the Notch pathway, vesicle transport and Alzheimer's disease. The latest findings appear in four papers in this issue2,3,4,5 with further results being reported at a Keystone meeting in March. These studies do not demonstrate that Notch signalling is directly relevant to Alzheimer's disease. But they do show that presenilins regulate both APP processing and Notch signalling by influencing unusual protein cleavage events.

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Figure 1: Proteolytic steps involved in the maturation of β-amyloid precursor protein (APP) and Notch.

References

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Authors and Affiliations

  1. Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, 32224, Florida, USA

    John Hardy

  2. Unité de Biologie Moléculaire de lExpression Génique, URA 1773 CNRS, Institut Pasteur, 25 rue du Dr Roux, Paris, Cedex 15 75724, France

    Alain Israël

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  1. John Hardy
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  2. Alain Israël
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Hardy, J., Israël, A. In search of γ-secretase . Nature 398, 466–467 (1999). https://doi.org/10.1038/18979

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