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

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, Alfredo G. Tomasselli, Luis A. Parodi, Robert L. Heinrikson and Mark E. Gurney ()
Additional contact information
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.

Nature, 1999, vol. 402, issue 6761, 533-537

Abstract: 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.

Date: 1999
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DOI: 10.1038/990107

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