Evidence that tumor necrosis factor α converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor

Joseph D. Buxbaum, Kang Nian Liu, Yuxia Luo, Jennifer L. Slack, Kim L. Stocking, Jacques J. Peschon, Richard S. Johnson, Beverly J. Castner, Douglas Pat Cerretti, Roy A. Black

Research output: Contribution to journalArticlepeer-review

834 Scopus citations

Abstract

The amyloid protein, Aβ, which accumulates in the brains of Alzheimer patients, is derived by proteolysis of the amyloid protein precursor (APP). APP can undergo endoproteolytic processing at three sites, one at the amino terminus of the Aβ domain (β-cleavage), one within the Aβ domain (α- cleavage), and one at the carboxyl terminus of the Aβ domain (γ-cleavage). The enzymes responsible for these activities have not been unambiguously identified. By the use of gene disruption (knockout), we now demonstrate that TACE (tumor necrosis factor α converting enzyme), a member of the ADAM family (a disintegrin and metalloprotease-family) of proteases, plays a central role in regulated α-cleavage of APP. Our data suggest that TACE may be the α-secretase responsible for the majority of regulated α-cleavage in cultured cells. Furthermore, we show that inhibiting this enzyme affects both APP secretion and Aβ formation in cultured cells.

Original languageEnglish
Pages (from-to)27765-27767
Number of pages3
JournalJournal of Biological Chemistry
Volume273
Issue number43
DOIs
StatePublished - 23 Oct 1998

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