| First Author | Muradashvili N | Year | 2014 |
| Journal | J Cereb Blood Flow Metab | Volume | 34 |
| Issue | 9 | Pages | 1472-82 |
| PubMed ID | 24865997 | Mgi Jnum | J:328489 |
| Mgi Id | MGI:6840523 | Doi | 10.1038/jcbfm.2014.102 |
| Citation | Muradashvili N, et al. (2014) Ablation of MMP9 gene ameliorates paracellular permeability and fibrinogen-amyloid beta complex formation during hyperhomocysteinemia. J Cereb Blood Flow Metab 34(9):1472-82 |
| abstractText | 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. |
