Letters to Nature

Nature 402, 533-537 (2 December 1999) | doi:10.1038/990107; Received 19 October 1999; Accepted 5 November 1999

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

Riqiang Yan1,2, Michael J. Bienkowski2,3, Mary E. Shuck3, Huiyi Miao1, Monica C. Tory3, Adele M. Pauley4, John R. Brashler5, Nancy C. Stratman4, W. Rodney Mathews6, Allen E. Buhl5, Donald B. Carter4, Alfredo G. Tomasselli7, Luis A. Parodi8, Robert L. Heinrikson7 & Mark E. Gurney4

  1. Cell & Molecular Biology,
  2. Genomics,
  3. Protein Sciences,
  4. Pharmacology,
  5. Structural, Analytical & Medicinal Chemistry and
  6. Neurobiology, Pharmacia & Upjohn, Inc., 301 Henrietta Street, Kalamazoo, MI 49007, USA
  7. Bioinformatics, Pharmacia & Upjohn, Inc., Lindhagensgatan 133, S-11287 Stockholm, Sweden
  8. These authors contributed equally to this work

Correspondence to: Riqiang Yan1,2Mark E. Gurney4 Correspondence and requests for materials should be addressed to R.Y. (e-mail: Email: riqiang.yan@am.pnu.com) or M.E.G. (e-mail: Email: mark.e.gurney@am.pnu.com). Sequences are deposited in GenBank under the following accession numbers: human Asp1, AF200342; human Asp2, AF200343; mouse Asp2, AF200346; human Asp3, AF200343; and human Asp4, AF200345.

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 beta- and gamma-secretases4, 5, 6, 7, generates the amyloid beta-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 beta-secretase activity. The Asp2 gene is expressed widely in brain and other tissues. Decreasing the expression of Asp2 in cells reduces amyloid beta-peptide production and blocks the accumulation of the carboxy-terminal APP fragment that is created by beta-secretase cleavage. Solubilized Asp2 protein cleaves a synthetic APP peptide substrate at the beta-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 beta-peptide peptide and the consequent formation of amyloid plaque in Alzheimer's disease.