Aicardi-Goutières syndrome (AGS) is a rare genetic disorder that affects the brain and immune system of paediatric patients. Clinical features of AGS include central nervous system (CNS) white matter abnormalities, developmental delays, progressive motor and cognitive decline, and elevated interferon-alpha (IFN-α) levels in cerebrospinal fluid, a hallmark feature of AGS. IFN-α is linked to disruptions in calcium homeostasis and chronic neuroinflammation, contributing to myelin and oligodendrocyte damage. To investigate white matter damage (WMD) and calcifications observed in AGS patients, we utilised transgenic (GIFN) mice with astrocyte-specific over-expression of IFN-α driven by GFAP protein as a preclinical model.

Brain tissue sections from two age groups of GIFN mice (2 and 7 months) were stained with Luxol Fast Blue (LFB), Hematoxylin & Eosin (H&E), Alizarin Red S (ARS), and immunofluorescence for IBA1 and ASPA. Age-related alterations were observed which correlates with disease severity. LFB revealed demyelination or areas of discolouration in the corpus callosum and cerebellar white matter of GIFN mice, alongside with dysregulation of myelin genes (MBP, PLP1, MOG, OLIG2 and SOX10) as determined by RT-qPCR analysis. H&E identified subtle micro-aneurysms specifically in the cerebellum. ARS highlighted sparse cerebellar calcifications, more pronounced in older GIFN mice, and immunofluorescence staining indicated neuroinflammation.

Our findings establish GIFN mice as a valid preclinical model of AGS, demonstrating myelin defects and micro-angiopathy similar to those observed in AGS patients. This model provides insights into AGS pathophysiology and potential therapeutic strategies targeting IFN-α-mediated neuroinflammation and WMD.