Ablation of MMP9 Gene Ameliorates Paracellular Permeability and Fibrinogen–Amyloid Beta Complex Formation during Hyperhomocysteinemia
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-A β) 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-A β 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 β 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 β 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.