A Novel Mouse Model for Cerebral Inflammatory Demyelination in X‐Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets

Objective X‐linked adrenoleukodystrophy (ALD) is caused by mutations in ABCD1 , a peroxisomal gene. More than half of males with an ABCD1 mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of disease mechanisms and therapy development. Methods We used immunoassays and immunohistochemistry to assess novel (interleukin 18 [IL‐18]) and established molecular markers in cerebrospinal fluid (CSF) and postmortem brain tissue from cALD patients. We generated a cALD phenotype in Abcd1‐ knockout mice using a 2‐hit method that combines cuprizone and experimental autoimmune encephalomyelitis models. We then used magnetic resonance imaging (MRI) and immunohistochemistry to assess the fidelity of cALD molecular markers in the mice. Results Human and mouse cALD lesions shared histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B‐cell infiltration, and astrogliosis. Compared to wild‐type controls, Abcd1 ‐knockout mice displayed more cerebral demyelination, blood–brain barrier disruption, and perivascular immune cell infiltration. This enhanced inflammatory response was associated with higher levels of fibrin deposition, oxidative stress, demyelination, and axonal injury. IL‐18 immunoreactivity co‐localized with perivascular monocytes/macrophages in both human and mouse brain tissue. In cALD patients, CSF IL‐18 levels correlated with MRI lesion severity. Interpretation Our results suggest loss of Abcd1 function in mice predisposes to more severe blood–brain barrier disruption, cerebral inflammation driven by the infiltration of peripheral immune cells, demyelination, and axonal damage, replicating human cALD features. This novel mouse model could shed light on cALD mechanisms and accelerate cALD therapy development. ANN NEUROL 2024