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

Autor: Christoph Harms, Nafisa M. Jadavji, Marco Foddis, Ulrich Dirnagl, Janet Lips, Philipp Boehm-Sturm, Ahmed A. Khalil, Martina Füchtemeier, Tracy D. Farr
Rok vydání: 2015
Předmět:
Carotid Artery Diseases
Male
Homocysteine
Morris water navigation task
physiopathology [Brain]
pathology [Folic Acid Deficiency]
Random Allocation
Behavioral Neuroscience
chemistry.chemical_compound
pathology [Brain]
physiopathology [Folic Acid Deficiency]
Gliosis
FADD
glial fibrillary astrocytic protein
mouse
Mice
Knockout
deficiency [Uracil-DNA Glycosidase]
biology
Learning Disabilities
Neurodegeneration
Brain
pathology [Gliosis]
metabolism [Matrix Metalloproteinase 9]
Matrix Metalloproteinase 9
Basilar Artery
physiopathology [Cognition Disorders]
Uracil-DNA glycosylase
Female
medicine.medical_specialty
blood [Homocysteine]
Nerve Tissue Proteins
Folic Acid Deficiency
blood supply [Brain]
physiology [Maze Learning]
medicine.artery
Internal medicine
Glial Fibrillary Acidic Protein
medicine
Basilar artery
Animals
ddc:610
Maze Learning
pathology [Basilar Artery]
Uracil-DNA Glycosidase
physiopathology [Learning Disabilities]
metabolism [Nerve Tissue Proteins]
physiopathology [Basilar Artery]
business.industry
Dentate gyrus
physiopathology [Cerebrovascular Disorders]
pathology [Learning Disabilities]
pathology [Cerebrovascular Disorders]
genetics [Uracil-DNA Glycosidase]
medicine.disease
physiopathology [Gliosis]
Diet
Mice
Inbred C57BL
Mmp9 protein
mouse
Cerebrovascular Disorders
Disease Models
Animal
Endocrinology
chemistry
DNA glycosylase
Chronic Disease
Immunology
biology.protein
pathology [Cognition Disorders]
Cognition Disorders
business
Zdroj: Behavioural brain research 283, 215-226 (2015). doi:10.1016/j.bbr.2015.01.040
ISSN: 0166-4328
DOI: 10.1016/j.bbr.2015.01.040
Popis: 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.
Databáze: OpenAIRE
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