Purification and cloning of amyloid precursor protein β-secretase from human brain

Sukanto Sinha (), John P. Anderson, Robin Barbour, Guriqbal S. Basi, Russell Caccavello, David Davis, Minhtam Doan, Harry F. Dovey, Normand Frigon, Jin Hong, Kirsten Jacobson-Croak, Nancy Jewett, Pamela Keim, Jeroen Knops, Ivan Lieberburg, Michael Power, Hua Tan, Gwen Tatsuno, Jay Tung, Dale Schenk, Peter Seubert, Susanna M. Suomensaari, Shuwen Wang, Donald Walker, Jun Zhao, Lisa McConlogue and Varghese John
Additional contact information
Sukanto Sinha: Elan Pharmaceuticals
John P. Anderson: Elan Pharmaceuticals
Robin Barbour: Elan Pharmaceuticals
Guriqbal S. Basi: Elan Pharmaceuticals
Russell Caccavello: Elan Pharmaceuticals
David Davis: Elan Pharmaceuticals
Minhtam Doan: Elan Pharmaceuticals
Harry F. Dovey: Elan Pharmaceuticals
Normand Frigon: Elan Pharmaceuticals
Jin Hong: Elan Pharmaceuticals
Kirsten Jacobson-Croak: Elan Pharmaceuticals
Nancy Jewett: Elan Pharmaceuticals
Pamela Keim: Elan Pharmaceuticals
Jeroen Knops: Elan Pharmaceuticals
Ivan Lieberburg: Elan Pharmaceuticals
Michael Power: Elan Pharmaceuticals
Hua Tan: Elan Pharmaceuticals
Gwen Tatsuno: Elan Pharmaceuticals
Jay Tung: Elan Pharmaceuticals
Dale Schenk: Elan Pharmaceuticals
Peter Seubert: Elan Pharmaceuticals
Susanna M. Suomensaari: Elan Pharmaceuticals
Shuwen Wang: Elan Pharmaceuticals
Donald Walker: Elan Pharmaceuticals
Jun Zhao: Elan Pharmaceuticals
Lisa McConlogue: Elan Pharmaceuticals
Varghese John: Elan Pharmaceuticals

Nature, 1999, vol. 402, issue 6761, 537-540

Abstract: Abstract Proteolytic processing of the amyloid precursor protein (APP) generates amyloid β (Aβ) peptide, which is thought to be causal for the pathology and subsequent cognitive decline in Alzheimer's disease. Cleavage by β-secretase at the amino terminus of the Aβ peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of β-cleaved soluble APP1, and a corresponding cell-associated carboxy-terminal fragment. Cleavage of the C-terminal fragment by γ-secretase(s) leads to the formation of Aβ. The pathogenic mutation K670M671 → N670L671 at the β-secretase cleavage site in APP2, which was discovered in a Swedish family with familial Alzheimer's disease, leads to increased β-secretase cleavage of the mutant substrate3. Here we describe a membrane-bound enzyme activity that cleaves full-length APP at the β-secretase cleavage site, and find it to be the predominant β-cleavage activity in human brain. We have purified this enzyme activity to homogeneity from human brain using a new substrate analogue inhibitor of the enzyme activity, and show that the purified enzyme has all the properties predicted for β-secretase. Cloning and expression of the enzyme reveals that human brain β-secretase is a new membrane-bound aspartic proteinase.

Date: 1999
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DOI: 10.1038/990114

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