Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil-DNA glycosylase impair learning in a mouse model of vascular cognitive impairment

Behav Brain Res. 2015 Apr 15:283:215-26. doi: 10.1016/j.bbr.2015.01.040. Epub 2015 Feb 2.


Dietary deficiencies in folic acid result in elevated levels of plasma homocysteine, which has been associated with the development of dementia and other neurodegenerative disorders. Previously, we have shown that elevated levels of plasma homocysteine in mice deficient for a DNA repair enzyme, uracil-DNA glycosylase (UNG), result in neurodegeneration. The goal of this study was to evaluate how deficiencies in folic acid and UNG along with elevated levels of homocysteine affect vascular cognitive impairment, via chronic hypoperfursion in an animal model. Ung(+/+) and Ung(-/-) mice were placed on either control (CD) or folic acid deficient (FADD) diets. Six weeks later, the mice either underwent implantation of microcoils around both common carotid arteries. Post-operatively, behavioral tests began at 3-weeks, angiography was measured after 5-weeks using MRI to assess vasculature and at completion of study plasma and brain tissue was collected for analysis. Learning impairments in the Morris water maze (MWM) were observed only in hypoperfused Ung(-/-) FADD mice and these mice had significantly higher plasma homocysteine concentrations. Interestingly, Ung(+/+) FADD produced significant remodeling of the basilar artery and arterial vasculature. Increased expression of GFAP was observed in the dentate gyrus of Ung(-/-) hypoperfused and FADD sham mice. Chronic hypoperfusion resulted in increased cortical MMP-9 protein levels of FADD hypoperfused mice regardless of genotypes. These results suggest that elevated levels of homocysteine only, as a result of dietary folic acid deficiency, don't lead to memory impairments and neurobiochemical changes. Rather a combination of either chronic hypoperfusion or UNG deficiency is required.

Keywords: Chronic hypoperfusion; Folate; Homocysteine; Matrix metalloproteinases-9; Morris watermaze; Uracil-DNA glycosylase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basilar Artery / pathology
  • Basilar Artery / physiopathology
  • Brain / blood supply
  • Brain / pathology
  • Brain / physiopathology
  • Carotid Artery Diseases
  • Cerebrovascular Disorders / pathology
  • Cerebrovascular Disorders / physiopathology*
  • Chronic Disease
  • Cognition Disorders / pathology
  • Cognition Disorders / physiopathology*
  • Diet
  • Disease Models, Animal
  • Female
  • Folic Acid Deficiency / pathology
  • Folic Acid Deficiency / physiopathology*
  • Glial Fibrillary Acidic Protein
  • Gliosis / pathology
  • Gliosis / physiopathology
  • Homocysteine / blood*
  • Learning Disabilities / pathology
  • Learning Disabilities / physiopathology*
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • Maze Learning / physiology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Tissue Proteins / metabolism
  • Random Allocation
  • Uracil-DNA Glycosidase / deficiency*
  • Uracil-DNA Glycosidase / genetics


  • Glial Fibrillary Acidic Protein
  • Nerve Tissue Proteins
  • glial fibrillary astrocytic protein, mouse
  • Homocysteine
  • Uracil-DNA Glycosidase
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse