title: Ablation of MMP9 gene ameliorates paracellular permeability and fibrinogen-amyloid beta complex formation during hyperhomocysteinemia.
abstract: 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-β-amyloid (Fg-Aβ) complex. Cerebrovascular permeability changes were assessed in C57BL/6J (wild type, WT), cystathionine-β-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-Aβ 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-Aβ 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-Aβ 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.
authors.affiliation: Department of Physiology and Biophysics, University of Louisville, School of Medicine, Louisville, Kentucky, USA.
authors.forename: Nino
authors.initials: N
authors.lastname: Muradashvili
authors.affiliation: Department of Physiology and Biophysics, University of Louisville, School of Medicine, Louisville, Kentucky, USA.
authors.forename: Reeta
authors.initials: R
authors.lastname: Tyagi
authors.affiliation: Department of Physiology and Biophysics, University of Louisville, School of Medicine, Louisville, Kentucky, USA.
authors.forename: Naira
authors.initials: N
authors.lastname: Metreveli
authors.affiliation: Department of Physiology and Biophysics, University of Louisville, School of Medicine, Louisville, Kentucky, USA.
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi
authors.affiliation: Department of Physiology and Biophysics, University of Louisville, School of Medicine, Louisville, Kentucky, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lominadze
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002199:Capillary Permeability; D002560:Cerebrovascular Circulation; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D020138:Hyperhomocysteinemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008570:Memory, Short-Term; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D016229:Amyloid beta-Peptides; D015703:Antigens, CD; D015820:Cadherins; D003541:Cystathionine beta-Synthase; D005340:Fibrinogen; D020780:Matrix Metalloproteinase 9; D046912:Multiprotein Complexes; D000099152:Cadherin 5; C501830:Mmp9 protein, mouse