Chronic interferon-alpha overexpression induces white matter damage and neurovascular abnormalities in a mouse model of Aicardi-Goutières syndrome.

Abstract

BACKGROUND: Aicardi-Goutières syndrome (AGS) is a rare leukodystrophy marked by chronic neuroinflammation, white matter (WM) injury, cerebral vasculopathy with calcifications, and progressive neurological decline. A central feature of AGS is sustained overexpression of interferon-alpha (IFN-α), yet its long-term impact on WM integrity remains poorly understood. To investigate this, we used a transgenic mouse model (GIFN) with astrocyte-specific expression of IFN-α that recapitulates key features of AGS. METHODS: Brain tissue from GIFN mice at 2 and 7 months of age, reflecting early and advanced disease stages, was analysed using haematoxylin and eosin (H&E), Alizarin Red S (ARS), Luxol Fast Blue (LFB), and immunofluorescence (IF) for IBA1 and ASPA. Quantitative PCR was used to assess expression of myelin-associated genes in the corpus callosum and cerebellum. RESULTS: H&E revealed microvascular abnormalities near WM tracts. ARS identified age-dependent calcifications in the corpus callosum and cerebellum. IF confirmed persistent microgliosis and neuroinflammation. WM degeneration was evidenced by demyelination and a significant reduction in OLIG2and ASPAoligodendrocytes. Gene expression analysis showed downregulation of key myelin-related genes (MBP, PLP1, MOG, OLIG2, SOX10), consistent with histological changes. CONCLUSION: Chronic astrocyte-driven IFN-α exposure leads to progressive WM pathology, including inflammation, demyelination, and oligodendrocyte loss. GIFN mice provide a robust model of AGS and offer new insights into the mechanisms by which sustained IFN-α disrupts myelin homeostasis. This model may aid in the development of therapeutic strategies for AGS and related interferonopathies.