Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-β peptide catabolism

Ke Jie Yin, John R. Cirrito, Ping Yan, Xiaoyan Hu, Qingli Xiao, Xiaoou Pan, Randall Bateman, Haowei Song, Fong Fu Hsu, John Turk, Jan Xu, Chung Y. Hsu, Jason C. Mills, David M. Holtzman, Jin Moo Lee

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219 Citations (Scopus)

Abstract

It has been postulated that the development of amyloid plaques in Alzheimer's disease (AD) may result from an imbalance between the generation and clearance of the amyloid-β peptide (Aβ). Although familial AD appears to be caused by Aβ overproduction, sporadic AD (the most prevalent form) may result from impairment in clearance. Recent evidence suggests that several proteases may contribute to the degradation of Aβ. Furthermore, astrocytes have recently been implicated as a potential cellular mediator of Aβ degradation. In this study, we examined the possibility that matrix metalloproteinases (MMPs), proteases known to be expressed and secreted by astrocytes, could play a role in extracellular Aβ degradation. We found that astrocytes surrounding amyloid plaques showed enhanced expression of MMP-2 and MMP-9 in aged amyloid precursor protein (APP)/presenilin 1 mice. Moreover, astrocyte-conditioned medium (ACM) degraded Aβ, lowering levels and producing several fragments after incubation with synthetic human Aβ1-40 and Aβ1-42. This activity was attenuated with specific inhibitors of MMP-2 and -9, as well as in ACM derived from mmp-2 or -9 knock-out (KO) mice. In vivo, significant increases in the steady-state levels of Aβ were found in the brains of mmp-2 and -9 KO mice compared with wild-type controls. Furthermore, pharmacological inhibition of the MMPs with N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide (GM 6001) increased brain interstitial fluid Aβ levels and elimination of half-life in APPsw mice. These results suggest that MMP-2 and -9 may contribute to extracellular brain Aβ clearance by promoting Aβ catabolism.

Original languageEnglish
Pages (from-to)10939-10948
Number of pages10
JournalJournal of Neuroscience
Volume26
Issue number43
DOIs
Publication statusPublished - Oct 25 2006

Keywords

  • Alzheimer's disease
  • Amyloid β clearance
  • Astrocytes
  • Laser-capture microdissection
  • Matrix metalloproteinases
  • Microdialysis

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Yin, K. J., Cirrito, J. R., Yan, P., Hu, X., Xiao, Q., Pan, X., Bateman, R., Song, H., Hsu, F. F., Turk, J., Xu, J., Hsu, C. Y., Mills, J. C., Holtzman, D. M., & Lee, J. M. (2006). Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-β peptide catabolism. Journal of Neuroscience, 26(43), 10939-10948. https://doi.org/10.1523/JNEUROSCI.2085-06.2006