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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Abstract

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.

Original languageEnglish
Pages (from-to)24566-24574
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number34
DOIs
Publication statusPublished - Aug 25 2006

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Matrix Metalloproteinase 9
Amyloid
Amyloid Plaques
Peptide Hydrolases
Brain
Insulysin
In Vitro Techniques
Neprilysin
Degradation
Aptitude
Endothelins
Matrix Metalloproteinases
Transmission Electron Microscopy
Astrocytes
Ionization
Mass spectrometry
Digestion
Desorption
Mass Spectrometry
Alzheimer Disease

ASJC Scopus subject areas

  • Biochemistry

Cite this

Yan, P., Hu, X., Song, H., Yin, K., Bateman, R. J., Cirrito, J. R., ... Lee, J. M. (2006). Matrix metalloproteinase-9 degrades amyloid-β fibrils in vitro and compact plaques in situ. Journal of Biological Chemistry, 281(34), 24566-24574. https://doi.org/10.1074/jbc.M602440200

Matrix metalloproteinase-9 degrades amyloid-β fibrils in vitro and compact plaques in situ. / Yan, Ping; Hu, Xiaoyan; Song, Haowei; Yin, Kejie; Bateman, Randall J.; Cirrito, John R.; Xiao, Qingli; Hsu, Fong F.; Turk, John W.; Xu, Jan; Hsu, Chung Y.; Holtzman, David M.; Lee, Jin Moo.

In: Journal of Biological Chemistry, Vol. 281, No. 34, 25.08.2006, p. 24566-24574.

Research output: Contribution to journalArticle

Yan, P, Hu, X, Song, H, Yin, K, Bateman, RJ, Cirrito, JR, Xiao, Q, Hsu, FF, Turk, JW, Xu, J, Hsu, CY, Holtzman, DM & Lee, JM 2006, 'Matrix metalloproteinase-9 degrades amyloid-β fibrils in vitro and compact plaques in situ', Journal of Biological Chemistry, vol. 281, no. 34, pp. 24566-24574. https://doi.org/10.1074/jbc.M602440200
Yan, Ping ; Hu, Xiaoyan ; Song, Haowei ; Yin, Kejie ; Bateman, Randall J. ; Cirrito, John R. ; Xiao, Qingli ; Hsu, Fong F. ; Turk, John W. ; Xu, Jan ; Hsu, Chung Y. ; Holtzman, David M. ; Lee, Jin Moo. / Matrix metalloproteinase-9 degrades amyloid-β fibrils in vitro and compact plaques in situ. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 34. pp. 24566-24574.
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