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@ARTICLE{Jadavji:137854,
author = {Jadavji, Nafisa M and Farr, Tracy D and Lips, Janet and
Khalil, Ahmed A and Boehm-Sturm, Philipp and Foddis, Marco
and Harms, Christoph and Füchtemeier, Martina and Dirnagl,
Ulrich},
title = {{E}levated levels of plasma homocysteine, deficiencies in
dietary folic acid and uracil-{DNA} glycosylase impair
learning in a mouse model of vascular cognitive impairment.},
journal = {Behavioural brain research},
volume = {283},
issn = {0166-4328},
address = {Amsterdam},
publisher = {Elsevier},
reportid = {DZNE-2020-04176},
pages = {215-226},
year = {2015},
abstract = {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 = {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 (NLM Chemicals) / Nerve Tissue Proteins (NLM
Chemicals) / glial fibrillary astrocytic protein, mouse (NLM
Chemicals) / Homocysteine (NLM Chemicals) / Uracil-DNA
Glycosidase (NLM Chemicals) / Matrix Metalloproteinase 9
(NLM Chemicals) / Mmp9 protein, mouse (NLM Chemicals)},
cin = {AG Dirnagl},
ddc = {610},
cid = {I:(DE-2719)1810002},
pnm = {344 - Clinical and Health Care Research (POF3-344)},
pid = {G:(DE-HGF)POF3-344},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:25655513},
doi = {10.1016/j.bbr.2015.01.040},
url = {https://pub.dzne.de/record/137854},
}