Evidence That Tumor Necrosis Factor α Converting Enzyme Is Involved in Regulated α-Secretase Cleavage of the Alzheimer Amyloid Protein Precursor

doi:10.1074/jbc.273.43.27765

Evidence That Tumor Necrosis Factor α Converting Enzyme Is Involved in Regulated α-Secretase Cleavage of the Alzheimer Amyloid Protein Precursor*

From the ^‡Departments of Psychiatry and Neurobiology, Mount Sinai School of Medicine, New York, New York 10029 and ^¶Immunex Corporation, Seattle, Washington 98101

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 disintegrinand 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.

Footnotes

↵* This work was supported by a James A. Shannon Director’s Award (to J. D. B.), an ADRC Pilot Project Award (to J. D. B.), and NIA, National Institutes of Health Grant AG14996 (to J. D. B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵§ To whom correspondence should be addressed: Dept. of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1230, New York, NY 10029. Tel.: 212-241-2693; Fax: 212-828-4221; E-mail:buxbaj01{at}doc.mssm.edu.
Abbreviations:

APP

amyloid protein precursor

APP_s

secreted APP

TNF-α

tumor necrosis factor α

TACE

TNF-α converting enzyme

IC3

Immunex compound 3

HPLC

high performance liquid chromatography

PMA

phorbol 12-myristate 13-acetate

PDBu

phorbol 12,13-dibutyrate

Tricine

N-[2-hydroxy-1,1-bis(hydroxymethyl) ethyl]glycine.
- Received July 28, 1998.
- Revision received August 28, 1998.
The American Society for Biochemistry and Molecular Biology, Inc.