title: Impaired gait pattern as a sensitive tool to assess hypoxic brain damage in a novel mouse model of atherosclerotic plaque rupture.
abstract: Apolipoprotein E deficient (ApoE(-/-)) mice with a heterozygous mutation in the fibrillin-1 gene (Fbn1(C1039G+/-)) show spontaneous atherosclerotic plaque ruptures, disturbances in cerebral flow and sudden death when fed a Western-type diet (WD). The present study focused on motor coordination and spatial learning of ApoE(-/-) Fbn1(C1039G+/-) mice on WD for 20 weeks (n=21). ApoE(-/-) mice on WD (n=24) and ApoE(-/-) Fbn1(C1039G+/-) mice on normal diet (ND, n=21) served as controls. Starting from 10 weeks of diet, coordination was assessed every two weeks by the following tests: gait analysis, stationary beam, wire suspension and accelerating rotarod. The Morris water maze test was performed after 13 weeks of diet to study spatial learning. At the end of the experiment (20 weeks of WD), the mice were sacrificed and the brachiocephalic artery and brain were isolated. From 12 weeks onward, gait analysis of ApoE(-/-) Fbn1(C1039G+/-) mice on WD revealed a progressive increase in track width as compared to ApoE(-/-) mice on WD and ApoE(-/-) Fbn1(C1039G+/-) mice on ND (at 20 weeks: 29.8±0.6 mm vs. 25.8±0.4 mm and 26.0±0.5 mm). Moreover, the stationary beam test showed a decrease in motor coordination of ApoE(-/-) Fbn1(C1039G+/-) mice on WD at 18 and 20 weeks. The wire suspension test and accelerating rotarod could not detect signs of motor impairment. Spatial learning was also not affected. Histological analysis of the brachiocephalic artery showed larger and more stenotic plaques in ApoE(-/-) Fbn1(C1039G+/-) mice on WD. Furthermore, the parietal cortex of ApoE(-/-) Fbn1(C1039G+/-) mice on WD showed pyknotic nuclei as a sign of hypoxia and the percentage of pyknosis correlated with track width. In conclusion, gait analysis may be an efficient method for analyzing hypoxic brain damage in the ApoE(-/-) Fbn1(C1039G+/-) mouse model. This test could be of value to assess the effect of potential anti-atherosclerotic therapies in mice.
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address: lynn.roth@uantwerpen.be.
authors.forename: Lynn
authors.initials: L
authors.lastname: Roth
authors.affiliation: Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Debby
authors.initials: D
authors.lastname: Van Dam
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Carole
authors.initials: C
authors.lastname: Van der Donckt
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Dorien M
authors.initials: DM
authors.lastname: Schrijvers
authors.affiliation: Laboratory of Pharmacology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Lemmens
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Van Brussel
authors.affiliation: Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium; Department of Neurology/Memory Clinic, Middelheim General Hospital, ZNA, Lindendreef 1, 2020 Antwerp, Belgium; Department of Neurology and Alzheimer Research Center, University Medical Center Groningen (UMCG), Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Martinet
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Guido R Y
authors.initials: GR
authors.lastname: De Meyer
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001696:Biomechanical Phenomena; D003645:Death, Sudden; D004195:Disease Models, Animal; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D005684:Gait / Q000502:physiology*; D002534:Hypoxia, Brain / Q000175:diagnosis* / Q000473:pathology / Q000503:physiopathology*; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000473:pathology / Q000502:physiology; D010296:Parietal Lobe / Q000473:pathology / Q000503:physiopathology; D058226:Plaque, Atherosclerotic / Q000473:pathology / Q000503:physiopathology*; D004856:Postural Balance / Q000502:physiology; D045442:Rotarod Performance Test; D012720:Severity of Illness Index; D065853:Spatial Learning / Q000502:physiology; D054392:Adipokines
chemical_list: D001057:Apolipoproteins E; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605724:Fbn1 protein, mouse; D054392:Adipokines
keywords: ApoE(−/−) Fbn1(C1039G+/−) mouse model; Atherosclerosis; Gait; Hypoxia; Motor coordination; Pyknosis