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Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity

Author

Listed:
  • Riqiang Yan

    (Cell & Molecular Biology)

  • Michael J. Bienkowski

    (Genomics)

  • Mary E. Shuck

    (Genomics)

  • Huiyi Miao

    (Cell & Molecular Biology)

  • Monica C. Tory

    (Genomics)

  • Adele M. Pauley

    (Neurobiology, Pharmacia & Upjohn, Inc.)

  • John R. Brashler

    (Pharmacology)

  • Nancy C. Stratman

    (Neurobiology, Pharmacia & Upjohn, Inc.)

  • W. Rodney Mathews

    (Structural, Analytical & Medicinal Chemistry)

  • Allen E. Buhl

    (Pharmacology)

  • Donald B. Carter

    (Neurobiology, Pharmacia & Upjohn, Inc.)

  • Alfredo G. Tomasselli

    (Protein Sciences)

  • Luis A. Parodi

    (Bioinformatics, Pharmacia & Upjohn, Inc.)

  • Robert L. Heinrikson

    (Protein Sciences)

  • Mark E. Gurney

    (Neurobiology, Pharmacia & Upjohn, Inc.)

Abstract

Mutations in the gene encoding the amyloid protein precursor (APP) cause autosomal dominant Alzheimer's disease1,2,3. Cleavage of APP by unidentified proteases, referred to as β- and γ-secretases4,5,6,7, generates the amyloid β-peptide, the main component of the amyloid plaques found in Alzheimer's disease patients8. The disease-causing mutations flank the protease cleavage sites in APP and facilitate its cleavage. Here we identify a new membrane-bound aspartyl protease (Asp2) with β-secretase activity. The Asp2 gene is expressed widely in brain and other tissues. Decreasing the expression of Asp2 in cells reduces amyloid β-peptide production and blocks the accumulation of the carboxy-terminal APP fragment that is created by β-secretase cleavage. Solubilized Asp2 protein cleaves a synthetic APP peptide substrate at the β-secretase site, and the rate of cleavage is increased tenfold by a mutation associated with early-onset Alzheimer's disease in Sweden3. Thus, Asp2 is a new protein target for drugs that are designed to block the production of amyloid β-peptide peptide and the consequent formation of amyloid plaque in Alzheimer's disease.

Suggested Citation

  • Riqiang Yan & Michael J. Bienkowski & Mary E. Shuck & Huiyi Miao & Monica C. Tory & Adele M. Pauley & John R. Brashler & Nancy C. Stratman & W. Rodney Mathews & Allen E. Buhl & Donald B. Carter & Alfr, 1999. "Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity," Nature, Nature, vol. 402(6761), pages 533-537, December.
  • Handle: RePEc:nat:nature:v:402:y:1999:i:6761:d:10.1038_990107
    DOI: 10.1038/990107
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