Abcd1 deficient mice are more likely to respond to cuprizone-induced demyelination in a model of X-linked adrenoleukodystrophy (X-ALD), according to a recently published study in Acta Neuropathologica Communications.
X-ALD is an inherited peroxisomal disease characterized by very long-chain fatty acids (VLCFAs) accumulation with varied clinical phenotypes. Unlike what occurs in long-chain fatty acid oxidation disorders (LCFAOD), the underlying physiopathological mechanism is an Abcd1 gene deficiency that encodes a VLCFA peroxisomal transporter.
The most severe variant of X-ALD is characterized by demyelination, inflammation, and oligodendrocyte loss in cerebral white matter, the researchers noted. However, the role of VLCFA accumulation and of Abcd1 deficient oligodendrocytes in the demyelinating pathophysiology has not been accurately determined, they added.
Read more about LCFAOD etiology
The authors administered the demyelinating agent cuprizone to Abcd1 deficient mice and to Abcd1 positive mice and compared the effects on each group. Cuprizone has been previously used in models investigating axonal demyelination models and phagocyte-driven demyelination and remyelination.
Results showed that a larger fraction of Abcd1 deficient mice experienced complete demyelination in comparison to Abcd1 positive mice after 3 weeks. After cuprizone withdrawal, both genotypes experienced satisfactory remyelination.
The authors used immunohistochemistry to assess the extent of oligodendrocyte loss in both mice models, observing that in Abcd1 deficient mice, there were fewer oligodendrocytes in the corpus callosum in comparison to the control group.
“Taken together, these data indicate that Abcd1 deficient oligodendrocytes exhibit a stronger response to cuprizone resulting in a faster drop in mature oligodendrocyte numbers. In addition to the loss of mature oligodendrocytes, cuprizone administration is associated with axonal pathology,” the authors wrote.
The authors noted that there was no significant difference in myelin loss between both groups of mice. There was no significant difference in microglia activation between both groups, suggesting that Abcd1 deficiency does not significantly influence microglial activation.
“Understanding the repercussions of the genetic Abcd1 deficiency in X-ALD on oligodendrocyte physiology in the context of demyelination might provide the groundwork for novel therapeutic strategies,” the authors concluded.
Martinović, K., Bauer, J., Kunze, M. et al. Abcd1 deficiency accelerates cuprizone-induced oligodendrocyte loss and axonopathy in a demyelinating mouse model of X-linked adrenoleukodystrophy. Acta Neuropathol Commun. Published online June 18, 2023. doi:10.1186/s40478-023-01595-w