TY - JOUR
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
Y1 - 2009/10
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.
AB - 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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U2 - 10.1124/jpet.109.154724
DO - 10.1124/jpet.109.154724
M3 - Article
C2 - 19587312
AN - SCOPUS:70349330693
SN - 0022-3565
VL - 331
SP - 14
EP - 22
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 1
ER -