title: Increased homocysteine levels impair reference memory and reduce cortical levels of acetylcholine in a mouse model of vascular cognitive impairment.
abstract: Folates are B-vitamins that are vital for normal brain function. Deficiencies in folates either genetic (methylenetetrahydrofolate reductase, MTHFR) or dietary intake of folic acid result in elevated levels of homocysteine. Clinical studies have shown that elevated levels of homocysteine (Hcy) may be associated with the development of dementia, however this link remains unclear. The purpose of this study was to evaluate the impact of increased Hcy levels on a mouse model of vascular cognitive impairment (VCI) produced by chronic hypoperfusion. Male and female Mthfr+/+and Mthfr+/-mice were placed on either control (CD) or folic acid deficient (FADD) diets after which all animals underwent microcoil implantation around each common carotid artery or a sham procedure. Post-operatively animals were tested on the Morris water maze (MWM), y-maze, and rotarod. Animals had no motor impairments on the rotarod, y-maze, and could learn the location of the platform on the MWM. However, on day 8 of testing of MWM testing during the probe trial, Mthfr+/-FADD microcoil mice spent significantly less time in the target quadrant when compared to Mthfr+/-CD sham mice, suggesting impaired reference memory. All FADD mice had elevated levels of plasma homocysteine. MRI analysis revealed arterial remodeling was present in Mthfr+/-microcoil mice not Mthfr+/+mice. Acetylcholine and related metabolites were reduced in cortical tissue because of microcoil implantation and elevated levels of homocysteine. Deficiencies in folate metabolism resulting in increased Hcy levels yield a metabolic profile that increases susceptibility to neurodegeneration in a mouse model of VCI.
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin, Charité University Medicine Berlin, Germany. Electronic address: kdam@rockefeller.edu.
authors.forename: Kevin
authors.initials: K
authors.lastname: Dam
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin, Charité University Medicine Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE) Berlin Site, Berlin, Germany. Electronic address: martina.fuechtemeier@dzne.de.
authors.forename: Martina
authors.initials: M
authors.lastname: Füchtemeier
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin, Charité University Medicine Berlin, Germany. Electronic address: T.Farr@nottingham.ac.uk.
authors.forename: Tracy D
authors.initials: TD
authors.lastname: Farr
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin, Charité University Medicine Berlin, Germany. Electronic address: philipp.boehm-sturm@charite.de.
authors.forename: Philipp
authors.initials: P
authors.lastname: Boehm-Sturm
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin, Charité University Medicine Berlin, Germany. Electronic address: marco.foddis@charite.de.
authors.forename: Marco
authors.initials: M
authors.lastname: Foddis
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin, Charité University Medicine Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE) Berlin Site, Berlin, Germany. Electronic address: ulrich.dirnagl@charite.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, USA. Electronic address: ovm4@cornell.edu.
authors.forename: Olga
authors.initials: O
authors.lastname: Malysheva
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, USA. Electronic address: mac379@cornell.edu.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Caudill
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin, Charité University Medicine Berlin, Germany; Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada. Electronic address: nafisa.jadavji@mail.mcgill.ca.
authors.forename: Nafisa M
authors.initials: NM
authors.lastname: Jadavji
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000098:blood supply / Q000000981:diagnostic imaging / Q000378:metabolism*; D015140:Dementia, Vascular / Q000000981:diagnostic imaging / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005494:Folic Acid Deficiency / Q000000981:diagnostic imaging / Q000378:metabolism / Q000523:psychology; D006710:Homocysteine / Q000378:metabolism*; D008297:Male; D008568:Memory / Q000502:physiology*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency / Q000235:genetics; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000378:metabolism / Q000523:psychology; D011897:Random Allocation
chemical_list: D006710:Homocysteine; C000609029:MTHFR protein, mouse; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D000109:Acetylcholine
keywords: Acetylcholine; Chronic hypoperfusion; Folic acid; Homocysteine; Methylenetetrahydrofolate reductase; Vascular cognitive impairment