Regulation of matrix metalloproteinase 2 by oligomeric amyloid β protein

Wenjun Li, Ethan Poteet, Luokun Xie, Ran Liu, Yi Wen, Shao Hua Yang

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Matrix metalloproteinases (MMPs) are a group of proteinases that degrade components of the extracellular matrix (ECM). There is increasing evidence for a link between the activation of MMPs and Alzheimer's disease (AD) pathogenesis, in which both beneficial and detrimental actions of MMPs have been suggested. It has been demonstrated that MMPs could degrade amyloid β (Aβ) and play important roles in the extracellular Aβ catabolism and clearance. On the other hand, MMPs could contribute to AD pathogenesis by compromising the blood brain barrier and promoting neurodegeneration. In the present study, we observed that oligomeric Aβ regulates MMP2 expression in a paradoxical manner. In rat primary astrocyte cultures, oligomeric Aβ down-regulated MMP2 transcription and reduced its extracellular activity. However, in a widely used mouse model for AD, immunohistochemistry demonstrated an increase of MMP2 expression in astrocytes surrounding senile plaques in APP/PS1 transgenic mice brains. Using real-time PCR, we found that the MMP2 mRNA level was elevated in APP/PS1 transgenic mice brains. In addition, elevated mRNA levels of MMP stimulating cytokines such as IL-1β and TGFβ were found in the brains of APP/PS1 mice. Our study suggests a complex regulation of MMP2 expression by oligomeric Aβ in astrocytes. While oligomeric Aβ directly down-regulates MMP2 expression and activation in astrocytes, it induces production of proinflammatory cytokines which could serve as strong stimulators for MMP2. Therefore, the ultimate outcome of the oligomeric Aβ on MMP2 activation in astrocytes might be the combination of its direct inhibitory action on astrocyte MMP2 expression and the secondary action of inducing inflammatory cytokines.

Original languageEnglish
Pages (from-to)141-148
Number of pages8
JournalBrain Research
Volume1387
DOIs
StatePublished - 28 Apr 2011

Fingerprint

Amyloidogenic Proteins
Matrix Metalloproteinase 2
Matrix Metalloproteinases
Astrocytes
Alzheimer Disease
Cytokines
Transgenic Mice
Brain
Messenger RNA
Amyloid Plaques
Blood-Brain Barrier
Interleukin-1
Amyloid
Extracellular Matrix
Real-Time Polymerase Chain Reaction
Peptide Hydrolases
Down-Regulation
Immunohistochemistry

Keywords

  • Amyloid β
  • Matrix metalloproteinase
  • Oligomeric Aβ
  • Primary astrocyte

Cite this

Li, Wenjun ; Poteet, Ethan ; Xie, Luokun ; Liu, Ran ; Wen, Yi ; Yang, Shao Hua. / Regulation of matrix metalloproteinase 2 by oligomeric amyloid β protein. In: Brain Research. 2011 ; Vol. 1387. pp. 141-148.
@article{2a84b69621fa440c941838035b7904d3,
title = "Regulation of matrix metalloproteinase 2 by oligomeric amyloid β protein",
abstract = "Matrix metalloproteinases (MMPs) are a group of proteinases that degrade components of the extracellular matrix (ECM). There is increasing evidence for a link between the activation of MMPs and Alzheimer's disease (AD) pathogenesis, in which both beneficial and detrimental actions of MMPs have been suggested. It has been demonstrated that MMPs could degrade amyloid β (Aβ) and play important roles in the extracellular Aβ catabolism and clearance. On the other hand, MMPs could contribute to AD pathogenesis by compromising the blood brain barrier and promoting neurodegeneration. In the present study, we observed that oligomeric Aβ regulates MMP2 expression in a paradoxical manner. In rat primary astrocyte cultures, oligomeric Aβ down-regulated MMP2 transcription and reduced its extracellular activity. However, in a widely used mouse model for AD, immunohistochemistry demonstrated an increase of MMP2 expression in astrocytes surrounding senile plaques in APP/PS1 transgenic mice brains. Using real-time PCR, we found that the MMP2 mRNA level was elevated in APP/PS1 transgenic mice brains. In addition, elevated mRNA levels of MMP stimulating cytokines such as IL-1β and TGFβ were found in the brains of APP/PS1 mice. Our study suggests a complex regulation of MMP2 expression by oligomeric Aβ in astrocytes. While oligomeric Aβ directly down-regulates MMP2 expression and activation in astrocytes, it induces production of proinflammatory cytokines which could serve as strong stimulators for MMP2. Therefore, the ultimate outcome of the oligomeric Aβ on MMP2 activation in astrocytes might be the combination of its direct inhibitory action on astrocyte MMP2 expression and the secondary action of inducing inflammatory cytokines.",
keywords = "Amyloid β, Matrix metalloproteinase, Oligomeric Aβ, Primary astrocyte",
author = "Wenjun Li and Ethan Poteet and Luokun Xie and Ran Liu and Yi Wen and Yang, {Shao Hua}",
year = "2011",
month = "4",
day = "28",
doi = "10.1016/j.brainres.2011.02.078",
language = "English",
volume = "1387",
pages = "141--148",
journal = "Brain Research",
issn = "0006-8993",
publisher = "Elsevier",

}

Regulation of matrix metalloproteinase 2 by oligomeric amyloid β protein. / Li, Wenjun; Poteet, Ethan; Xie, Luokun; Liu, Ran; Wen, Yi; Yang, Shao Hua.

In: Brain Research, Vol. 1387, 28.04.2011, p. 141-148.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Regulation of matrix metalloproteinase 2 by oligomeric amyloid β protein

AU - Li, Wenjun

AU - Poteet, Ethan

AU - Xie, Luokun

AU - Liu, Ran

AU - Wen, Yi

AU - Yang, Shao Hua

PY - 2011/4/28

Y1 - 2011/4/28

N2 - Matrix metalloproteinases (MMPs) are a group of proteinases that degrade components of the extracellular matrix (ECM). There is increasing evidence for a link between the activation of MMPs and Alzheimer's disease (AD) pathogenesis, in which both beneficial and detrimental actions of MMPs have been suggested. It has been demonstrated that MMPs could degrade amyloid β (Aβ) and play important roles in the extracellular Aβ catabolism and clearance. On the other hand, MMPs could contribute to AD pathogenesis by compromising the blood brain barrier and promoting neurodegeneration. In the present study, we observed that oligomeric Aβ regulates MMP2 expression in a paradoxical manner. In rat primary astrocyte cultures, oligomeric Aβ down-regulated MMP2 transcription and reduced its extracellular activity. However, in a widely used mouse model for AD, immunohistochemistry demonstrated an increase of MMP2 expression in astrocytes surrounding senile plaques in APP/PS1 transgenic mice brains. Using real-time PCR, we found that the MMP2 mRNA level was elevated in APP/PS1 transgenic mice brains. In addition, elevated mRNA levels of MMP stimulating cytokines such as IL-1β and TGFβ were found in the brains of APP/PS1 mice. Our study suggests a complex regulation of MMP2 expression by oligomeric Aβ in astrocytes. While oligomeric Aβ directly down-regulates MMP2 expression and activation in astrocytes, it induces production of proinflammatory cytokines which could serve as strong stimulators for MMP2. Therefore, the ultimate outcome of the oligomeric Aβ on MMP2 activation in astrocytes might be the combination of its direct inhibitory action on astrocyte MMP2 expression and the secondary action of inducing inflammatory cytokines.

AB - Matrix metalloproteinases (MMPs) are a group of proteinases that degrade components of the extracellular matrix (ECM). There is increasing evidence for a link between the activation of MMPs and Alzheimer's disease (AD) pathogenesis, in which both beneficial and detrimental actions of MMPs have been suggested. It has been demonstrated that MMPs could degrade amyloid β (Aβ) and play important roles in the extracellular Aβ catabolism and clearance. On the other hand, MMPs could contribute to AD pathogenesis by compromising the blood brain barrier and promoting neurodegeneration. In the present study, we observed that oligomeric Aβ regulates MMP2 expression in a paradoxical manner. In rat primary astrocyte cultures, oligomeric Aβ down-regulated MMP2 transcription and reduced its extracellular activity. However, in a widely used mouse model for AD, immunohistochemistry demonstrated an increase of MMP2 expression in astrocytes surrounding senile plaques in APP/PS1 transgenic mice brains. Using real-time PCR, we found that the MMP2 mRNA level was elevated in APP/PS1 transgenic mice brains. In addition, elevated mRNA levels of MMP stimulating cytokines such as IL-1β and TGFβ were found in the brains of APP/PS1 mice. Our study suggests a complex regulation of MMP2 expression by oligomeric Aβ in astrocytes. While oligomeric Aβ directly down-regulates MMP2 expression and activation in astrocytes, it induces production of proinflammatory cytokines which could serve as strong stimulators for MMP2. Therefore, the ultimate outcome of the oligomeric Aβ on MMP2 activation in astrocytes might be the combination of its direct inhibitory action on astrocyte MMP2 expression and the secondary action of inducing inflammatory cytokines.

KW - Amyloid β

KW - Matrix metalloproteinase

KW - Oligomeric Aβ

KW - Primary astrocyte

UR - http://www.scopus.com/inward/record.url?scp=79954422020&partnerID=8YFLogxK

U2 - 10.1016/j.brainres.2011.02.078

DO - 10.1016/j.brainres.2011.02.078

M3 - Article

C2 - 21376707

AN - SCOPUS:79954422020

VL - 1387

SP - 141

EP - 148

JO - Brain Research

JF - Brain Research

SN - 0006-8993

ER -