Matrix metalloproteinase-9 degrades amyloid-β fibrils in vitro and compact plaques in situ

Ping Yan, Xiaoyan Hu, 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, Jin Moo Lee

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308 引文 斯高帕斯(Scopus)

摘要

The pathological hallmark of Alzheimer disease is the senile plaque principally composed of tightly aggregated amyloid-β fibrils (fAβ), which are thought to be resistant to degradation and clearance. In this study, we explored whether proteases capable of degrading soluble Aβ (sAβ) could degrade fAβ as well. We demonstrate that matrix metalloproteinase-9 (MMP-9) can degrade fAβ and that this ability is not shared by other sAβ-degrading enzymes examined, including endothelin-converting enzyme, insulin-degrading enzyme, and neprilysin. fAβ was decreased in samples incubated with MMP-9 compared with other proteases, assessed using thioflavin-T. Furthermore, fAβ breakdown with MMP-9 but not with other proteases was demonstrated by transmission electron microscopy. Proteolytic digests of purified fAβ were analyzed with matrix-assisted laser desorption ionization time-of-flight mass spectrometry to identify sites of Aβ that are cleaved during its degradation. Only MMP-9 digests contained fragments (Aβ1-20 and Aβ1-30) from fAβ1-42 substrate; the corresponding cleavage sites are thought to be important for β-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 fAβ and may contribute to ongoing clearance of plaques from amyloid-laden brains.
原文英語
頁(從 - 到)24566-24574
頁數9
期刊Journal of Biological Chemistry
281
發行號34
DOIs
出版狀態已發佈 - 8月 25 2006

ASJC Scopus subject areas

  • 生物化學

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