TY  - JOUR
AU  - Jadavji, Nafisa M
AU  - Farr, Tracy D
AU  - Lips, Janet
AU  - Khalil, Ahmed A
AU  - Boehm-Sturm, Philipp
AU  - Foddis, Marco
AU  - Harms, Christoph
AU  - Füchtemeier, Martina
AU  - Dirnagl, Ulrich
TI  - Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil-DNA glycosylase impair learning in a mouse model of vascular cognitive impairment.
JO  - Behavioural brain research
VL  - 283
SN  - 0166-4328
CY  - Amsterdam
PB  - Elsevier
M1  - DZNE-2020-04176
SP  - 215-226
PY  - 2015
AB  - 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.
KW  - Animals
KW  - Basilar Artery: pathology
KW  - Basilar Artery: physiopathology
KW  - Brain: blood supply
KW  - Brain: pathology
KW  - Brain: physiopathology
KW  - Carotid Artery Diseases
KW  - Cerebrovascular Disorders: pathology
KW  - Cerebrovascular Disorders: physiopathology
KW  - Chronic Disease
KW  - Cognition Disorders: pathology
KW  - Cognition Disorders: physiopathology
KW  - Diet
KW  - Disease Models, Animal
KW  - Female
KW  - Folic Acid Deficiency: pathology
KW  - Folic Acid Deficiency: physiopathology
KW  - Glial Fibrillary Acidic Protein
KW  - Gliosis: pathology
KW  - Gliosis: physiopathology
KW  - Homocysteine: blood
KW  - Learning Disabilities: pathology
KW  - Learning Disabilities: physiopathology
KW  - Male
KW  - Matrix Metalloproteinase 9: metabolism
KW  - Maze Learning: physiology
KW  - Mice, Inbred C57BL
KW  - Mice, Knockout
KW  - Nerve Tissue Proteins: metabolism
KW  - Random Allocation
KW  - Uracil-DNA Glycosidase: deficiency
KW  - Uracil-DNA Glycosidase: genetics
KW  - Glial Fibrillary Acidic Protein (NLM Chemicals)
KW  - Nerve Tissue Proteins (NLM Chemicals)
KW  - glial fibrillary astrocytic protein, mouse (NLM Chemicals)
KW  - Homocysteine (NLM Chemicals)
KW  - Uracil-DNA Glycosidase (NLM Chemicals)
KW  - Matrix Metalloproteinase 9 (NLM Chemicals)
KW  - Mmp9 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25655513
DO  - DOI:10.1016/j.bbr.2015.01.040
UR  - https://pub.dzne.de/record/137854
ER  -