PMID- 24865997
OWN - NLM
STAT- MEDLINE
DCOM- 20141031
LR  - 20220223
IS  - 1559-7016 (Electronic)
IS  - 0271-678X (Print)
IS  - 0271-678X (Linking)
VI  - 34
IP  - 9
DP  - 2014 Sep
TI  - Ablation of MMP9 gene ameliorates paracellular permeability and 
      fibrinogen-amyloid beta complex formation during hyperhomocysteinemia.
PG  - 1472-82
LID - 10.1038/jcbfm.2014.102 [doi]
AB  - Increased blood level of homocysteine (Hcy), called hyperhomocysteinemia (HHcy) 
      accompanies many cognitive disorders including Alzheimer's disease. We 
      hypothesized that HHcy-enhanced cerebrovascular permeability occurs via 
      activation of matrix metalloproteinase-9 (MMP9) and leads to an increased 
      formation of fibrinogen-beta-amyloid (Fg-Abeta) complex. Cerebrovascular permeability 
      changes were assessed in C57BL/6J (wild type, WT), cystathionine-beta-synthase 
      heterozygote (Cbs+/-, a genetic model of HHcy), MMP9 gene knockout (Mmp9-/-), and 
      Cbs and Mmp9 double knockout (Cbs+/-/Mmp9-/-) mice using a dual-tracer probing 
      method. Expression of vascular endothelial cadherin (VE-cadherin) and Fg-Abeta 
      complex formation was assessed in mouse brain cryosections by 
      immunohistochemistry. Short-term memory of mice was assessed with a novel object 
      recognition test. The cerebrovascular permeability in Cbs+/- mice was increased 
      via mainly the paracellular transport pathway. VE-cadherin expression was the 
      lowest and Fg-Abeta complex formation was the highest along with the diminished 
      short-term memory in Cbs+/- mice. These effects of HHcy were ameliorated in 
      Cbs+/-/Mmp9-/- mice. Thus, HHcy causes activation of MMP9 increasing 
      cerebrovascular permeability by downregulation of VE-cadherin resulting in an 
      enhanced formation of Fg-Abeta complex that can be associated with loss of memory. 
      These data may lead to the identification of new targets for therapeutic 
      intervention that can modulate HHcy-induced cerebrovascular permeability and 
      resultant pathologies.
FAU - Muradashvili, Nino
AU  - Muradashvili N
AD  - Department of Physiology and Biophysics, University of Louisville, School of 
      Medicine, Louisville, Kentucky, USA.
FAU - Tyagi, Reeta
AU  - Tyagi R
AD  - Department of Physiology and Biophysics, University of Louisville, School of 
      Medicine, Louisville, Kentucky, USA.
FAU - Metreveli, Naira
AU  - Metreveli N
AD  - Department of Physiology and Biophysics, University of Louisville, School of 
      Medicine, Louisville, Kentucky, USA.
FAU - Tyagi, Suresh C
AU  - Tyagi SC
AD  - Department of Physiology and Biophysics, University of Louisville, School of 
      Medicine, Louisville, Kentucky, USA.
FAU - Lominadze, David
AU  - Lominadze D
AD  - Department of Physiology and Biophysics, University of Louisville, School of 
      Medicine, Louisville, Kentucky, USA.
LA  - eng
GR  - R01 NS084823/NS/NINDS NIH HHS/United States
GR  - R01 HL071010/HL/NHLBI NIH HHS/United States
GR  - R01 NS051568/NS/NINDS NIH HHS/United States
GR  - P30 GM103507/GM/NIGMS NIH HHS/United States
GR  - HL-071010/HL/NHLBI NIH HHS/United States
GR  - NS-084823/NS/NINDS NIH HHS/United States
GR  - NS-051568/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140528
PL  - United States
TA  - J Cereb Blood Flow Metab
JT  - Journal of cerebral blood flow and metabolism : official journal of the 
      International Society of Cerebral Blood Flow and Metabolism
JID - 8112566
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Antigens, CD)
RN  - 0 (Cadherins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (cadherin 5)
RN  - 9001-32-5 (Fibrinogen)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - EC 3.4.24.35 (Mmp9 protein, mouse)
RN  - EC 4.2.1.22 (Cystathionine beta-Synthase)
SB  - IM
MH  - Alzheimer Disease/genetics/metabolism/pathology/physiopathology
MH  - Amyloid beta-Peptides/genetics/*metabolism
MH  - Animals
MH  - Antigens, CD/genetics/metabolism
MH  - Cadherins/genetics/metabolism
MH  - *Capillary Permeability
MH  - *Cerebrovascular Circulation
MH  - Cystathionine beta-Synthase/genetics/metabolism
MH  - Enzyme Activation/genetics
MH  - Fibrinogen/genetics/*metabolism
MH  - Gene Expression Regulation/genetics
MH  - Hyperhomocysteinemia/genetics/*metabolism/pathology/physiopathology
MH  - Matrix Metalloproteinase 9/genetics/*metabolism
MH  - Memory, Short-Term
MH  - Mice
MH  - Mice, Knockout
MH  - Multiprotein Complexes/genetics/*metabolism
PMC - PMC4158659
EDAT- 2014/05/29 06:00
MHDA- 2014/11/02 06:00
PMCR- 2015/09/01
CRDT- 2014/05/29 06:00
PHST- 2013/12/02 00:00 [received]
PHST- 2014/04/22 00:00 [revised]
PHST- 2014/05/01 00:00 [accepted]
PHST- 2014/05/29 06:00 [entrez]
PHST- 2014/05/29 06:00 [pubmed]
PHST- 2014/11/02 06:00 [medline]
PHST- 2015/09/01 00:00 [pmc-release]
AID - jcbfm2014102 [pii]
AID - 10.1038/jcbfm.2014.102 [doi]
PST - ppublish
SO  - J Cereb Blood Flow Metab. 2014 Sep;34(9):1472-82. doi: 10.1038/jcbfm.2014.102. 
      Epub 2014 May 28.