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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265 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
頁(從 - 到)10939-10948
頁數10
期刊Journal of Neuroscience
26
發行號43
DOIs
出版狀態已發佈 - 10月 25 2006

ASJC Scopus subject areas

  • 神經科學 (全部)

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