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J. Biol. Chem., Vol. 281, Issue 34, 24566-24574, August 25, 2006

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Matrix Metalloproteinase-9 Degrades Amyloid- Fibrils in Vitro and Compact Plaques in Situ^*

Ping Yan¹, Xiaoyan Hu¹, Haowei Song, Kejie Yin, Randall J. Bateman, John R. Cirrito, Qingli Xiao, Fong F. Hsu, John W. Turk, Jan Xu, Chung Y. Hsu^¶, David M. Holtzman^||, and Jin-Moo Lee²

From the Department of Neurology and the Hope Center for Neurological Disorders, Division of Endocrinology, Diabetes, Metabolism, and Lipid Research, Department of Internal Medicine, ^||Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110 and the ^¶Taipei Medical University, Taipei, Taiwan

The pathological hallmark of Alzheimer disease is the senile plaque principally composed of tightly aggregated amyloid- fibrils (fA), which are thought to be resistant to degradation and clearance. In this study, we explored whether proteases capable of degrading soluble A (sA) could degrade fA as well. We demonstrate that matrix metalloproteinase-9 (MMP-9) can degrade fA and that this ability is not shared by other sA-degrading enzymes examined, including endothelin-converting enzyme, insulin-degrading enzyme, and neprilysin. fA was decreased in samples incubated with MMP-9 compared with other proteases, assessed using thioflavin-T. Furthermore, fA breakdown with MMP-9 but not with other proteases was demonstrated by transmission electron microscopy. Proteolytic digests of purified fA were analyzed with matrix-assisted laser desorption ionization time-of-flight mass spectrometry to identify sites of A that are cleaved during its degradation. Only MMP-9 digests contained fragments (A_1-20 and A_1-30) from fA_1-42 substrate; the corresponding cleavage sites are thought to be important for -pleated sheet formation. To determine whether MMP-9 can degrade plaques formed in vivo, fresh brain slices from aged APP/PS1 mice were incubated with proteases. MMP-9 digestion resulted in a decrease in thioflavin-S (ThS) staining. Consistent with a role for endogenous MMP-9 in this process in vivo, MMP-9 immunoreactivity was detected in astrocytes surrounding amyloid plaques in the brains of aged APP/PS1 and APPsw mice, and increased MMP activity was selectively observed in compact ThS-positive plaques. These findings suggest that MMP-9 can degrade fA and may contribute to ongoing clearance of plaques from amyloid-laden brains.

Received for publication, March 15, 2006 , and in revised form, June 1, 2006.

^* This work was supported by United States Public Health Service Grants P41-RR00954, P60-DK20579, and P30-DK56341 (to J. W. T.) and by National Institutes of Health Grants AG13956 (to D. M. H.) and NS048283 (to J.-M. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Neurology and the Hope Center for Neurological Disorders, Washington University, 660 South Euclid Ave., Campus Box 8111, St. Louis, MO 63110. Tel.: 314-747-1138; Fax: 314-747-1345; E-mail: leejm{at}neuro.wustl.edu.

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