title: Age-related decline in oligodendrogenesis retards white matter repair in mice.
abstract: OBJECTIVE
  Aging is one of the major risk factors for white matter injury in cerebrovascular disease. However, the effects of age on the mechanisms of injury/repair in white matter remain to be fully elucidated. Here, we ask whether, compared with young brains, white matter regions in older brains may be more vulnerable in part because of decreased rates of compensatory oligodendrogenesis after injury.
  
  
  METHODS
  A mouse model of prolonged cerebral hypoperfusion was prepared by bilateral common carotid artery stenosis in 2-month and 8-month-old mice. Matching in vitro studies were performed by subjecting oligodendrocyte precursor cells to sublethal 7-day CoCl2 treatment to induce chemical hypoxic stress.
  
  
  RESULTS
  Baseline myelin density in the corpus callosum was similar in 2-month and 8-month-old mice. But after induction of prolonged cerebral hypoperfusion, older mice showed more severe white matter injury together with worse deficits in working memory. The numbers of newborn oligodendrocytes and their precursors were increased by cerebral hypoperfusion in young mice, whereas these endogenous responses were significantly dampened in older mice. Defects in cyclic AMP response element-binding protein signaling may be involved because activating cyclic AMP response element-binding protein with the type-III phosphodiesterase inhibitor cilostazol in older mice restored the differentiation of oligodendrocyte precursor cells, alleviated myelin loss, and improved cognitive dysfunction during cerebral hypoperfusion. Cell culture systems confirmed that cilostazol promoted the differentiation of oligodendrocyte precursor cells.
  
  
  CONCLUSIONS
  An age-related decline in cyclic AMP response element-binding protein-mediated oligodendrogenesis may compromise endogenous white matter repair mechanisms, and therefore, drugs that activate cyclic AMP response element-binding protein signaling provide a potential therapeutic approach for treating white matter injury in aging brains.
authors.affiliation: Department of Radiology and Neurology, Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School, MA, USA.
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Miyamoto
authors.forename: Loc-Duyen D
authors.initials: LD
authors.lastname: Pham
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Toshinori
authors.initials: T
authors.lastname: Matsuzaki
authors.forename: Ji Hae
authors.initials: JH
authors.lastname: Seo
authors.forename: Caroline
authors.initials: C
authors.lastname: Magnain
authors.forename: Cenk
authors.initials: C
authors.lastname: Ayata
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
authors.forename: David
authors.initials: D
authors.lastname: Boas
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.forename: Ken
authors.initials: K
authors.lastname: Arai
mesh_terms: D000375:Aging / Q000473:pathology / Q000502:physiology*; D000818:Animals; D016587:Antimutagenic Agents / Q000008:administration & dosage / Q000633:toxicity; D002478:Cells, Cultured; D003035:Cobalt / Q000008:administration & dosage / Q000633:toxicity; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D003337:Corpus Callosum / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D002534:Hypoxia, Brain / Q000139:chemically induced / Q000150:complications; D056784:Leukoencephalopathies / Q000150:complications / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology; D058953:Neural Stem Cells / Q000187:drug effects / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*
chemical_list: D016587:Antimutagenic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D018696:Neuroprotective Agents; D003035:Cobalt; C018021:cobaltous chloride
keywords: aging; animal model; cyclic AMP response element-binding protein; oligodendrocyte; white matter diseases