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- Title
Matrix Metalloproteinases Expressed by Astrocytes Mediate Extracellular Amyloid-β Peptide Catabolism.
- Authors
Ke-Jie Yin; Cirrito, John R.; Ping Yan; Xiaoyun Hu; Qingli Xiao; Xiaoou Pan; Bateman, Randall; Haowei Song; Fong-Fu Hsu; Turk, John; Jan Xu; Hsu, Chung Y.; Mills, Jason C.; Holtzman, David M.; Jin-Moo Lee
- Abstract
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-βpeptide (Aβ). Although familial AD appears to be caused by Aβoverproduction, 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 Aβdegradation. 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 Aβdegradation.Wefound 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 Aβlevels and elimination of half-life in APPsw mice. These results suggest that MMP-2 and -9 may contribute to extracellular brain Aβclearance by promoting Aβcatabolism.
- Subjects
AMYLOID; ALZHEIMER'S disease; ASTROCYTES; METALLOPROTEINASES; PROTEOLYTIC enzymes
- Publication
Journal of Neuroscience, 2006, Vol 26, Issue 43, p10939
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.2085-06.2006