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Originally published In Press as doi:10.1074/jbc.M008793200 on November 17, 2000

J. Biol. Chem., Vol. 276, Issue 6, 4476-4484, February 9, 2001
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The Protease Inhibitor, MG132, Blocks Maturation of the Amyloid Precursor Protein Swedish Mutant Preventing Cleavage by beta -Secretase*

Michelle L. SteinhilbDagger §, R. Scott Turner, and James R. GautDagger ||

From the Dagger  Institute of Gerontology and Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109 and the  Department of Neurology, University of Michigan Medical Center, Ann Arbor, Michigan 48109 and Veterans Affairs Medical Center Geriatric Research, Education, and Clinical Center, Ann Arbor, Michigan 48105

Amyloid (Abeta ) peptides found aggregated into plaques in Alzheimer's disease are derived from the sequential cleavage of the amyloid precursor protein (APP) first by beta - and then by gamma -secretases. Peptide aldehydes, which inhibit cysteine proteases and proteasomes, reportedly block Abeta peptide secretion by interfering with gamma -secretase cleavage. Using a novel, specific, and sensitive enzyme-linked immunosorbent assay for the beta -secretase-cleaved fragment of the Swedish mutant of APP (APPSw), we determined that the peptide aldehyde, MG132, prevented beta -secretase cleavage. This block in beta -secretase cleavage was not observed with clasto-lactacystin beta -lactone and thus, cannot be attributed to proteasomal inhibition. MG132 inhibition of beta -secretase cleavage was compared with the serine protease inhibitor, 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF). AEBSF inhibition of beta -secretase cleavage was immediate and did not affect alpha -secretase cleavage. With MG132, inhibition was delayed and it decreased secretion of alpha -cleaved APPSw as well. Furthermore, MG132 treatment impaired maturation of full-length APPSw. Both inhibited intracellular formation of the beta -cleaved product. These results suggest that peptide aldehydes such as MG132 have multiple effects on the maturation and processing of APP. We conclude that the MG132-induced decrease in beta -secretase cleavage of APPSw is due to a block in maturation. This is sufficient to explain the previously reported peptide aldehyde-induced decrease in Abeta peptide secretion.

* This work was supported in part by a Michigan Alzheimer's Disease Research Center pilot grant (to J. R. G.).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.

§ Recipient of an Institute of Gerontology training fellowship (through Grant T32AG00114 from NIA, National Institutes of Health).

|| To whom correspondence should be addressed: Inst. of Gerontology and Dept. of Biological Chemistry, University of Michigan, 300 N. Ingalls, Rm. 973, Ann Arbor, MI 48109. Tel.: 734-764-3250; E-mail: jrgaut@umich.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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