Matrix Metalloprotease-9 Inhibition Improves Amyloid β-Mediated Cognitive Impairment and Neurotoxicity in Mice

  1. Hiroyuki Mizoguchi,
  2. Kazuhiro Takuma,
  3. Emiko Fukuzaki,
  4. Daisuke Ibi,
  5. Eiichi Someya,
  6. Ko-hei Akazawa,
  7. Tursun Alkam,
  8. Hiroko Tsunekawa,
  9. Akihiro Mouri,
  10. Yukihiro Noda,
  11. Toshitaka Nabeshima and
  12. Kiyofumi Yamada
  1. Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan (H.M., K.T., E.F., D.I., E.S., K.A., K.Y.); Futuristic Environmental Simulation Center, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan (H.M.); Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (K.T.); Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan (D.I., T.A., H.T., A.M., K.Y.); Division of Clinical Science in Clinical Pharmacy Practice, Management and Research, Faculty of Pharmacy, Meijo University, Nagoya, Japan (Y.N.); and Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan (T.N.)
  1. Address correspondence to:
    Dr. Kiyofumi Yamada, Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8560, Japan. E-mail: kyamada{at}med.nagoya-u.ac.jp

Abstract

In Alzheimer's disease (AD), the expression of matrix metalloproteases (MMPs), which are capable of degrading extracellular matrix proteins, is increased in the brain. Previous studies with cultured glial cells have demonstrated that amyloid β (Aβ) protein can induce the expression of MMPs, which could be involved in the degradation of Aβ. In the present study, we investigated the role of MMP-2 and MMP-9 in cognitive impairment induced by the injection of Aβ in mice. The intracerebroventricular injection of Aβ25-35, Aβ1-40, and Aβ1-42, but not Aβ40-1, transiently increased MMP-9, but not MMP-2, activity and protein expression in the hippocampus. Immunohistochemistry revealed the expression of MMP-9 to be increased in both neurons and glial cells in the hippocampus after Aβ treatment. The Aβ-induced cognitive impairment in vivo as well as neurotoxicity in vitro was significantly alleviated in MMP-9 homozygous knockout mice and by treatment with MMP inhibitors. These results suggest the increase in MMP-9 expression in the hippocampus to be involved in the development of cognitive impairment induced by Aβ1-40. Thus, specific inhibitors of MMP-9 may have therapeutic potential for the treatment of AD. Our findings suggest that, as opposed to expectations based on previous findings, MMP-9 plays a causal role in Aβ-induced cognitive impairment and neurotoxicity.

Footnotes

  • ↵Graphic The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • This study was supported in part by Grants-in-Aid for Scientific Research [Grants 18790052, 19390062]; the 21st Century Center of Excellence Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan; a grant from the Smoking Research Foundation, Japan; the Mochida Memorial Foundation for Medical and Pharmaceutical Research; the Suzuken Memorial Foundation; the Kanzawa Medical Research Foundation; the Japan Society for the Promotion of Science and Korea Science and Engineering Foundation under the Japan-Korea Basic Scientific Cooperation Program; the Academic Frontier Project for Private Universities; matching fund subsidy from Ministry of Education, Culture, Sports, Science and Technology [Grant 2007-2011]; and the Research on Risk of Chemical Substances, Health and Labor Science Research grants supported by the Ministry of Health, Labor and Welfare.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • ABBREVIATIONS:

    • Received April 7, 2009.
    • Accepted July 7, 2009.
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  1. Published online before print July 8, 2009, doi: 10.1124/jpet.109.154724 JPET October 2009 vol. 331 no. 1 14-22
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