Matrix metalloprotease-9 inhibition improves amyloid β-mediated cognitive impairment and neurotoxicity in mice

Hiroyuki Mizoguchi, Kazuhiro Takuma, Emiko Fukuzaki, Daisuke Ibi, Eiichi Someya, Ko Hei Akazawa, Tursun Alkam, Hiroko Tsunekawa, Akihiro Mouri, Yukihiro Noda, Toshitaka Nabeshima, Kiyofumi Yamada

研究成果: Article

50 引用 (Scopus)

抄録

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.

元の言語English
ページ(範囲)14-22
ページ数9
ジャーナルJournal of Pharmacology and Experimental Therapeutics
331
発行部数1
DOI
出版物ステータスPublished - 01-10-2009

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Metalloproteases
Amyloid
Hippocampus
Neuroglia
Inhibition (Psychology)
Cognitive Dysfunction
Alzheimer Disease
Serum Amyloid A Protein
Injections
Extracellular Matrix Proteins
Therapeutics
Knockout Mice
Cultured Cells
Immunohistochemistry
Neurons

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

これを引用

Mizoguchi, Hiroyuki ; Takuma, Kazuhiro ; Fukuzaki, Emiko ; Ibi, Daisuke ; Someya, Eiichi ; Akazawa, Ko Hei ; Alkam, Tursun ; Tsunekawa, Hiroko ; Mouri, Akihiro ; Noda, Yukihiro ; Nabeshima, Toshitaka ; Yamada, Kiyofumi. / Matrix metalloprotease-9 inhibition improves amyloid β-mediated cognitive impairment and neurotoxicity in mice. :: Journal of Pharmacology and Experimental Therapeutics. 2009 ; 巻 331, 番号 1. pp. 14-22.
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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.",
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Mizoguchi, H, Takuma, K, Fukuzaki, E, Ibi, D, Someya, E, Akazawa, KH, Alkam, T, Tsunekawa, H, Mouri, A, Noda, Y, Nabeshima, T & Yamada, K 2009, 'Matrix metalloprotease-9 inhibition improves amyloid β-mediated cognitive impairment and neurotoxicity in mice', Journal of Pharmacology and Experimental Therapeutics, 巻. 331, 番号 1, pp. 14-22. https://doi.org/10.1124/jpet.109.154724

Matrix metalloprotease-9 inhibition improves amyloid β-mediated cognitive impairment and neurotoxicity in mice. / Mizoguchi, Hiroyuki; Takuma, Kazuhiro; Fukuzaki, Emiko; Ibi, Daisuke; Someya, Eiichi; Akazawa, Ko Hei; Alkam, Tursun; Tsunekawa, Hiroko; Mouri, Akihiro; Noda, Yukihiro; Nabeshima, Toshitaka; Yamada, Kiyofumi.

:: Journal of Pharmacology and Experimental Therapeutics, 巻 331, 番号 1, 01.10.2009, p. 14-22.

研究成果: Article

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T1 - Matrix metalloprotease-9 inhibition improves amyloid β-mediated cognitive impairment and neurotoxicity in mice

AU - Mizoguchi, Hiroyuki

AU - Takuma, Kazuhiro

AU - Fukuzaki, Emiko

AU - Ibi, Daisuke

AU - Someya, Eiichi

AU - Akazawa, Ko Hei

AU - Alkam, Tursun

AU - Tsunekawa, Hiroko

AU - Mouri, Akihiro

AU - Noda, Yukihiro

AU - Nabeshima, Toshitaka

AU - Yamada, Kiyofumi

PY - 2009/10/1

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N2 - 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.

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