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 Yan^1,2Mark 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.

Abstract

Mutations in the gene encoding the amyloid protein precursor (APP) cause autosomal dominant Alzheimer's disease^{1, 2, 3}. Cleavage of APP by unidentified proteases, referred to as - and -secretases^{4, 5, 6, 7}, generates the amyloid -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 -secretase activity. The Asp2 gene is expressed widely in brain and other tissues. Decreasing the expression of Asp2 in cells reduces amyloid -peptide production and blocks the accumulation of the carboxy-terminal APP fragment that is created by -secretase cleavage. Solubilized Asp2 protein cleaves a synthetic APP peptide substrate at the -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 -peptide peptide and the consequent formation of amyloid plaque in Alzheimer's disease.