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The Journal of Neuroscience, October 25, 2006, 26(43):10939-10948; doi:10.1523/JNEUROSCI.2085-06.2006

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Neurobiology of Disease
Matrix Metalloproteinases Expressed by Astrocytes Mediate Extracellular Amyloid- Peptide Catabolism

Ke-Jie Yin,¹ John R. Cirrito,^1,2 Ping Yan,¹ Xiaoyan Hu,¹ Qingli Xiao,¹ Xiaoou Pan,^3,4 Randall Bateman,¹ Haowei Song,⁵ Fong-Fu Hsu,⁵ John Turk,⁵ Jan Xu,¹ Chung Y Hsu,⁶ Jason C. Mills,^3,4 David M. Holtzman,^1,3 and Jin-Moo Lee¹

¹Department of Neurology and the Hope Center for Neurological Disorders, and Departments of ²Psychiatry, ³Molecular Biology and Pharmacology, ⁴Pathology and Immunology, and ⁵Internal Medicine, Division of Endocrinology, Diabetes, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110, and ⁶Taipei Medical University, Taipei City, Taiwan 110

Correspondence should be addressed to Dr. Jin-Moo Lee, Department of Neurology, Campus Box 8111, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. Email: leejm{at}neuro.wustl.edu

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- peptide (A). Although familial AD appears to be caused by A 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 A. Furthermore, astrocytes have recently been implicated as a potential cellular mediator of A 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 A 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 A, lowering levels and producing several fragments after incubation with synthetic human A_1–40 and A_1–42. 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 A 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 A levels and elimination of half-life in APPsw mice. These results suggest that MMP-2 and -9 may contribute to extracellular brain A clearance by promoting A catabolism.

Key words: Alzheimer's disease; amyloid clearance; astrocytes; laser-capture microdissection; matrix metalloproteinases; microdialysis

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Received May 16, 2006; revised Aug. 17, 2006; accepted Sept. 17, 2006.

Correspondence should be addressed to Dr. Jin-Moo Lee, Department of Neurology, Campus Box 8111, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. Email: leejm{at}neuro.wustl.edu

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