A genetic mouse model of adult-onset, pervasive central nervous system demyelination with robust remyelination

Brain, 2010 · DOI: 10.1093/brain/awq247 · Published: September 17, 2010

Simple Explanation

This study introduces a new mouse model for studying demyelination and remyelination in the central nervous system (CNS). By inducing the expression of diphtheria toxin A subunit (DT-A) in adult oligodendrocytes, the researchers caused widespread oligodendrocyte loss and demyelination in the CNS of the mice. The mice initially developed severe ataxia and tremor, which correlated with impaired axonal conduction in the spinal cord. However, the animals demonstrated a remarkable ability to fully recover from these motor and physiological defects. This recovery was associated with extensive oligodendrocyte replenishment and widespread remyelination, highlighting the robust reparative potential of myelin in the CNS. The model is a promising tool for assessing therapies that promote remyelination.

Study Duration

70-77 days

Participants

PLP/CreERT; ROSA26-eGFP-DTA mice

Evidence Level

Not specified

Key Findings

1
The study successfully generated a mouse model with inducible oligodendrocyte ablation in adulthood, leading to demyelination.
2
Demyelination in the mice led to initial severe motor deficits, but was followed by spontaneous and robust remyelination and functional recovery.
3
The model demonstrates that oligodendrocyte loss and demyelination are not sufficient to trigger T cell infiltration during the most active phase of the disease.

Research Summary

The study introduces a novel mouse model of CNS demyelination achieved through cell-specific activation of diphtheria toxin A (DT-A) expression in adult oligodendrocytes. This leads to widespread oligodendrocyte loss and demyelination. The mice initially exhibit severe motor deficits, but strikingly, they fully recover, displaying extensive oligodendrocyte replenishment and widespread remyelination, showcasing the CNS's robust reparative capacity. This model allows for reversible demyelination and provides a valuable platform for developing and assessing therapeutic strategies for treating demyelinating diseases, with high reproducibility and clear quantitative behavioral readouts.

Practical Implications

Therapeutic Development

The mouse model provides a reproducible system for testing new therapies aimed at promoting remyelination in demyelinating diseases like multiple sclerosis.

Understanding Remyelination

The model can be used to study the mechanisms that control remyelination in the CNS and to identify factors that contribute to its age-related decline.

Axonal Protection

The model can help elucidate how oligodendrocytes provide trophic support to axons, potentially independent of myelination.

Study Limitations

1
The exact mechanisms of gender-related differences in vulnerability to oligodendrocyte loss are unclear.
2
The model does not fully replicate the inflammatory aspects of multiple sclerosis, as T cell infiltration is not observed during the active phase of demyelination.
3
Preliminary data indicate that older mice fail to remyelinate effectively, suggesting an age-related decline in remyelination potential that needs further investigation.

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