Genetically induced adult oligodendrocyte cell death is associated with poor myelin clearance, reduced remyelination, and axonal damage.
Loss of oligodendrocytes is a feature of many demyelinating diseases including multiple sclerosis. Here, we have established and characterized a novel model of genetically induced adult oligodendrocyte death. Specific primary loss of adult oligodendrocytes leads to a well defined and highly reproducible course of disease development that can be followed longitudinally by magnetic resonance imaging. Histological and ultrastructural analyses revealed progressive myelin vacuolation, in parallel to disease development that includes motor deficits, tremor, and ataxia. Myelin damage and clearance were associated with induction of oligodendrocyte precursor cell proliferation, albeit with some regional differences. Remyelination was present in the mildly affected corpus callosum. Consequences of acutely induced cell death of adult oligodendrocytes included secondary axonal damage. Microglia were activated in affected areas but without significant influx of B-cells, T-helper cells, or T-cytotoxic cells. Analysis of the model on a RAG-1 (recombination activating gene-1)-deficient background, lacking functional lymphocytes, did not change the observed disease and pathology compared with immune-competent mice. We conclude that this model provides the opportunity to study the consequences of adult oligodendrocyte death in the absence of primary axonal injury and reactive cells of the adaptive immune system. Our results indicate that if the blood-brain barrier is not disrupted, myelin debris is not removed efficiently, remyelination is impaired, and axonal integrity is compromised, likely as the result of myelin detachment. This model will allow the evaluation of strategies aimed at improving remyelination to foster axon protection.
Institute of Cell Biology, Department Biology, Eidgenössische Technische Hochschule (ETH) Zürich, CH-8093 Zürich, Switzerland.
Hartmut B F
HB
Pohl
Cristina
C
Porcheri
Thomas
T
Mueggler
Lukas C
LC
Bachmann
Gianvito
G
Martino
Dieter
D
Riethmacher
Robin J M
RJ
Franklin
Markus
M
Rudin
Ueli
U
Suter
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count; D016923:Cell Death / Q000235:genetics*; D003337:Corpus Callosum / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D005455:Fluorescent Antibody Technique; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008854:Microscopy, Electron; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology*; D045442:Rotarod Performance Test
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