Abstract 13197: Hyperhomocysteinemia Enhances Fibrinogen-beta Amyloid-Collagen Complex Formation Causing Loss of Short Memory in Mice
It is known that high level of homocysteine (Hcy), called hyperhomocysteinemia (HHcy) is associated with vascular dementia, seizure, stroke, and Alzheimer disease (AD). Although a strong association between amyloid- (A) peptide and fibrinogen (Fg) during AD is well-documented, the mechanism of amyloid plaque formation and deposition is unclear. We hypothesized HHcy increases cerebrovascular permeability affecting mainly the paracellular transport through downregulation of junction proteins, particularly vascular endothelial cadherine (VE-cadherin), via activation of matrix metalloproteinase-9 (MMP-9) and leading to vascular remodeling enhancing formation of Fg-A plaques on collagen.
Male wild type (WT, C57BL/6J), cystathionine β-synthase heterozygote (CBS+/-, a genetic model of HHcy), MMP-9 gene knockout (MMP9-/-), and CBS and MMP-9 double-knockout (CBS+/-/MMP9-/-) mice were used in this study. Prevailing role of paracellular transport was tasted by a dual-tracer probing method. Brain cortical cryo-sections were evaluated for expression of VE-cadherin and for Fg-Aβ-collagen plaque formation with immunohistochemistry. Novel object recognition test (NORT) was used to assess short memory of mice.
The results suggest that pial venular permeability was via mainly the paracellular transport pathway in CBS+/- mice, where protein leakage was greater and VE-cadherin expression was lowest than those in other animal groups. Expressions of Fg, Aβ, and collagen and their co-localization (plaque formation) were greater in CBS+/- mice compared to those in control animals. These effects were ameliorated in CBS+/-/MMP9-/- mice. NORT data showed that HHcy intensifies while the absence of MMP-9 activity mitigates the loss of short memory in mice.
Thus, our data show a novel mechanistic role of Hcy in loss of memory: HHcy causes downregulation of VE-cadherin increasing protein crossing of vascular wall through MMP-9 activation and leading to enhanced Fg-Aβ complex accumulation on vascular collagen matrix.
- © 2013 by American Heart Association, Inc.