title: Functional outcome is impaired following traumatic brain injury in aging Nogo-A/B-deficient mice.
abstract: Increasing age is associated with a poor prognosis following traumatic brain injury (TBI). CNS axons may recover poorly following TBI due to expression of myelin-derived inhibitors to axonal outgrowth such as Nogo-A. To study the role of Nogo-A/B in the pathophysiological response of the elderly to TBI, 1-year-old mice deficient in Nogo-A/B (Nogo-A/B homozygous(-/-) mice), Nogo-A/B heterozygous(-/+) mice, and age-matched wild-type (WT) littermate controls were subjected to a controlled cortical impact (CCI) TBI. Sham-injured WT mice (7 months old) and 12 month old naïve Nogo-A/B(-/-) and Nogo-A/B(-/+) served as controls. Neurological motor function was evaluated up to 3 weeks, and cognitive function, hemispheric tissue loss, myelin staining and hippocampal beta-amyloid (A beta) immunohistochemistry were evaluated at 4 weeks post-injury. In WT littermates, TBI significantly impaired learning ability at 4 weeks and neurological motor function up to 2 weeks post-injury and caused a significant loss of hemispheric tissue. Following TBI, Nogo-A/B(-/-) mice showed significantly less recovery from neurological motor and cognitive deficits compared to brain-injured WT mice. Naïve Nogo-A/B(-/-) and Nogo-A/B(-/+) mice quickly learned the MWM task in contrast to brain-injured Nogo-A/B(-/-) mice who failed to learn the MWM task at 4 weeks post-injury. Hemispheric tissue loss and cortical lesion volume were similar among the brain-injured genotypes. Neither TBI nor the absence of NogoA/B caused an increased A beta expression. Myelin staining showed a reduced area and density in the corpus callosum in brain-injured Nogo-A/B(-/-) animals compared to their littermate controls. These novel and unexpected behavioral results demonstrate that the absence of Nogo-A/B may negatively influence outcome, possibly related to hypomyelination, following TBI in mice and suggest a complex role for this myelin-associated axonal growth inhibitor following TBI.
authors: Traumatic Brain Injury Laboratory, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA 19104, USA. niklas.marklund@neurokir.uu.se
authors: N
authors: N
authors: Marklund
authors: D
authors: D
authors: Morales
authors: F
authors: F
authors: Clausen
authors: A
authors: A
authors: Hånell
authors: O
authors: O
authors: Kiwanuka
authors: A
authors: A
authors: Pitkänen
authors: D A
authors: DA
authors: Gimbel
authors: O
authors: O
authors: Philipson
authors: L
authors: L
authors: Lannfelt
authors: L
authors: L
authors: Hillered
authors: S M
authors: SM
authors: Strittmatter
authors: T K
authors: TK
authors: McIntosh
mesh_terms: D000375:Aging; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology*; D003072:Cognition Disorders / Q000473:pathology / Q000503:physiopathology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D009483:Neuropsychological Tests; D000070798:Nogo Proteins; D009929:Organ Size; D011897:Random Allocation; D020127:Recovery of Function / Q000502:physiology*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D016229:Amyloid beta-Peptides; D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603201:Rtn4 protein, mouse