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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