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-b-amyloid (Fg-Ab) complex. Cerebrovascular permeability changes were assessed in C57BL/6J (wild type, WT), cystathionine-b-synthase heterozygote (Cbs þ / À , a genetic model of HHcy), MMP9 gene knockout (Mmp9 À / À ), and Cbs and Mmp9 double knockout (Cbs þ / À /Mmp9 À / À ) mice using a dual-tracer probing method. Expression of vascular endothelial cadherin (VE-cadherin) and Fg-Ab 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 þ / À mice was increased via mainly the paracellular transport pathway. VE-cadherin expression was the lowest and Fg-Ab complex formation was the highest along with the diminished short-term memory in Cbs þ / À mice. These effects of HHcy were ameliorated in Cbs þ / À /Mmp9 À / À mice. Thus, HHcy causes activation of MMP9 increasing cerebrovascular permeability by downregulation of VE-cadherin resulting in an enhanced formation of Fg-Ab 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.

Betaine prevents homocysteine-induced memory impairment via matrix metalloproteinase-9 in the frontal cortex

“…Another researcher reported that the plasma activities of MMP-9 might be related to oxidative stress in patients [49]. Furthermore, abnormally expressed MMP-9 might implicated in diseases such as AD [50][51][52] and HHcy [53]. These findings suggest that HHcy increases oxidative stress, which results in enhanced levels of MMP-9 that are associated with the loss of memory.…”

Functional regions of Candida albicans hyphal cell wall protein Als3 that determine interaction with the oral bacterium Streptococcus gordonii

“…Intriguingly, where deletion of AFR did impair Als3 function was in binding to ECM proteins, although these effects were weaker than those observed for disruption of the N-terminal region or CRD. There is precedent for interactions of ECM proteins such as fibrinogen or collagen with amyloids in neuropathies or cognitive conditions such as Alzheimer's (Misumi et al, 2012;Muradashvili et al, 2014).…”

KDM4B histone demethylase and G9a regulate expression of vascular adhesion proteins in cerebral microvessels

“…A recent report showed that controlling neutrophil binding to brain microvessels, by blocking integrin activity, retarded AD pathogenesis and mitigated memory loss13. Muradashvili et al 44. reported that increased cerebrovascular permeability through downregulation of VE-cadherin was associated with memory loss.…”