Ablation of MMP9 gene ameliorates paracellular permeability and fibrinogen-amyloid beta complex formation during hyperhomocysteinemia

Increased blood level of homocysteine (Hcy), called hypethomocysteinemia (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-A beta) 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-A beta 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-A beta 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-A beta 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.