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Alzheimer's disease

A technical KO of amyloid-β peptide

Nature volume 391, pages 339–340 (1998)Cite this article

Research into the molecular mechanisms of Alzheimer's disease — the most common late-life dementia — continues to illuminate intriguing issues in protein biology, while seeking to identify therapeutic targets. These twin outcomes are exemplified by the exciting results of De Strooper and co-workers1, reported on page 387 of this issue. The authors show that the presenilin-1 (PS1) gene, mutations in which cause an aggressive form of early-onset familial Alzheimer's disease2,3, regulates the unusual intramembranous proteolysis of the amyloid precursor protein (APP). PS1 might, therefore, serve as an unexpected target for drugs against the disease.

Presenilin proteins span the membrane six to eight times. They are proteolytically processed to produce stable amino- and carboxy-terminal fragments2, which form a heterodimeric complex that seems to be biologically relevant (Fig. 1)4. Work on the nematode Caenorhabditis elegans indicates that presenilins are involved physiologically in cell-fate decisions through the Notch signalling pathway2. In support of this, deletion of the PS1 gene in mice produces a fatal developmental defect that closely resembles the phenotype seen in Notch knockout mice5,6.

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Figure 1: The influence of presenilin-1 (PS1) on proteolytic processing of the amyloid precursor protein (APP).
Figure 2: Model for the two-site cleavage of the sterol regulatory element binding protein (SREBP).

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Authors and Affiliations

  1. the Department of Molecular Biology, Central Institute for Mental Health, J5, D-68159, Mannheim, Germany

    Christian Haass

  2. the Center for Neurologic Diseases, Harvard Medical School, Brigham and Womens Hospital, Boston, 02115, Massachusetts, USA

    Dennis J. Selkoe

Authors
  1. Christian Haass
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  2. Dennis J. Selkoe
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Haass, C., Selkoe, D. A technical KO of amyloid-β peptide. Nature 391, 339–340 (1998). https://doi.org/10.1038/34800

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