Ablation of MMP9 gene ameliorates paracellular permeability and fibrinogen-amyloid beta complex formation during hyperhomocysteinemia
Related Experiment Video
Updated: Apr 29, 2026
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
Nino Muradashvili1, Reeta Tyagi1, Naira Metreveli1
1Department of Physiology and Biophysics, University of Louisville, School of Medicine, Louisville, Kentucky, USA.
Insights
High homocysteine (HHcy) levels increase brain vessel permeability by activating MMP9, leading to fibrinogen-amyloid complexes and memory loss. Blocking MMP9 in HHcy mice improved memory and reduced vessel leakage.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Hyperhomocysteinemia (HHcy) is linked to cognitive disorders like Alzheimer's disease.
- Elevated homocysteine may compromise cerebrovascular integrity.
- Matrix metalloproteinase-9 (MMP9) is implicated in vascular remodeling and breakdown.
Purpose of the Study:
- To investigate the role of MMP9 in HHcy-induced cerebrovascular permeability.
- To determine the impact of HHcy and MMP9 on fibrinogen-amyloid complex formation and memory.
- To explore therapeutic targets for HHcy-related cognitive decline.
Main Methods:
- Utilized genetic mouse models: wild type, HHcy (Cbs+/-), MMP9 knockout (Mmp9-/-), and double knockout (Cbs+/-/Mmp9-/-).
- Assessed cerebrovascular permeability using a dual-tracer method.
- Evaluated VE-cadherin expression and fibrinogen-amyloid complex formation via immunohistochemistry.
- Tested short-term memory using a novel object recognition test.
Main Results:
- HHcy (Cbs+/- mice) significantly increased cerebrovascular permeability, primarily via paracellular pathways.
- HHcy led to decreased VE-cadherin expression and increased fibrinogen-amyloid complex formation.
- These HHcy-induced deficits, including diminished short-term memory, were ameliorated in double knockout mice (Cbs+/-/Mmp9-/-).
Conclusions:
- HHcy activates MMP9, increasing cerebrovascular permeability through VE-cadherin downregulation.
- This process enhances fibrinogen-amyloid complex formation, potentially contributing to memory loss.
- Targeting MMP9 may offer a therapeutic strategy for HHcy-associated cognitive impairments and cerebrovascular pathologies.
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.
