慢性干扰素-α过表达在Aicardi-Goutières综合征的小鼠模型中会导致白质损伤和神经血管异常

《Experimental Parasitology》：Chronic interferon-alpha overexpression induces white matter damage and neurovascular abnormalities in a mouse model of Aicardi-Goutières syndrome

　　本研究利用GIFN转基因小鼠模型，分析了持续IFN-α表达对中枢神经系统中枢神经炎症、血管病变、白质脱髓鞘及少突胶质细胞减少的影响，发现其通过激活JAK/STAT通路导致慢性神经炎症，并伴随血管损伤、钙化及髓鞘发育异常。该模型为AGS等干扰素相关疾病提供了新的研究工具。

　　
Aicardi-Goutières syndrome (AGS) is a rare neuroinflammatory disorder characterised by progressive white matter (WM) degeneration, microvascular damage, and cerebral calcifications. The study utilised a transgenic mouse model (GIFN) expressing interferon-alpha (IFN-α) specifically in astrocytes to investigate the long-term effects of sustained IFN-α overexpression on WM integrity. Key findings include the development of age-dependent microangiopathy, calcifications, microglial activation, and progressive oligodendrocyte depletion, which collectively underscore the role of chronic IFN-α in driving WM pathology.

The study begins by establishing the GIFN mouse model as a relevant tool for AGS research. These mice recapitulate AGS pathophysiology through astrocyte-specific IFN-α overexpression, which mirrors the elevated IFN-α levels observed in AGS patients. The model was evaluated at two disease stages: 2 months (early) and 7 months (late), corresponding to initial and advanced pathological phases in AGS. Histological and molecular analyses were performed across the cerebellum and corpus callosum, key regions affected in AGS.

Microvascular abnormalities were identified in both cerebellar and callosal WM of GIFN mice. H&E staining revealed thickened capillary walls, perivascular infiltrates, and vessel occlusions, particularly in the retrosplenial cortex and periventricular regions. These vascular changes likely result from chronic IFN-α-induced endothelial dysfunction, a phenomenon supported by prior studies linking IFN-α to vascular inflammation in neurological disorders. The severity of microangiopathy increased with age, aligning with the progressive nature of AGS in humans.

Calcifications were observed in multiple brain regions of GIFN mice, with the cerebellum showing the most pronounced accumulation. Alizarin Red S staining detected focal calcium deposits in the cerebellar WM and retrosplenial cortex, particularly in aged mice. This mirrors the cerebral calcifications seen in AGS patients and suggests a shared pathogenic mechanism involving IFN-α-mediated vascular injury and impaired calcium homeostasis.

Microglial activation was a consistent finding across both age groups. IBA1 immunohistochemistry revealed hypertrophic microglia with elongated processes, a hallmark of chronic neuroinflammation. The intensity of IBA1 staining correlated with disease progression, with aged GIFN mice showing significantly elevated signal in the cerebellum and corpus callosum. This activation likely exacerbates WM damage through pro-inflammatory cytokine secretion and oxidative stress, as previously reported in other IFN-α-driven pathologies.

The most striking finding was the progressive depletion of oligodendrocytes, the cells responsible for myelin production. Stereological analyses demonstrated a significant reduction in OLIG2+ (total oligodendrocytes) and ASPA+ (mature oligodendrocytes) cell counts in the cerebellum and corpus callosum of GIFN mice, particularly at 7 months of age. This loss was accompanied by reduced myelin density, as confirmed by Luxol Fast Blue staining and quantification of myelin-associated genes (MBP, PLP1, MOG). The downregulation of these genes at both young and old ages indicates a persistent干扰机制 that disrupts myelin synthesis and maintenance.

Gene expression analysis revealed region-specific dysregulation of myelin-related genes. In the cerebellum, MBP, PLP1, OLIG2, and SOX10 were significantly reduced in young GIFN mice, with MBP and PLP1 remaining downregulated in older mice. In contrast, MOG expression declined in both cerebellum and corpus callosum, suggesting differential sensitivity of myelin subtypes to IFN-α. The upregulation of OLIG2 in aged mice at 7 months may reflect compensatory mechanisms or OPC maturation failure, warranting further investigation.

The study also highlighted vascular calcifications, a rare but critical feature of AGS. The accumulation of calcium deposits in the cerebellum and retrosplenial cortex was age-dependent, reaching peak severity in 7-month-old mice. This calcification process likely involves endothelial damage, impaired vascular repair mechanisms, and excessive calcium flux, as supported by prior research linking IFN-α to vascular mineralisation.

The regional specificity of pathology in GIFN mice merits attention. Cerebellar WM exhibited more severe oligodendrocyte loss and myelin degeneration compared to the corpus callosum. This could reflect differential vulnerability of glial cells to IFN-α toxicity or variations in BBB permeability, which may exacerbate vascular damage in the cerebellum. Additionally, the corpus callosum showed segmental differences, with the genu and splenium regions more affected than the body, suggesting spatial heterogeneity in WM pathology.

The study addresses a critical knowledge gap regarding the mechanisms of WM degeneration in AGS. Prior research focused on IFN-α's role in inflammation and immune dysregulation, but this work provides direct evidence of its causal link to vascular injury, microglial activation, and oligodendrocyte loss. The discovery of calcifications in WM further expands the known pathological spectrum of AGS, offering new therapeutic targets.

Limitations of the study include the reliance on a transgenic model, which may not fully replicate the genetic heterogeneity of human AGS. Additionally, the analysis of oligodendrocyte dynamics was limited to OLIG2 and ASPA markers, without differentiation between precursor and mature cells. Future studies could benefit from multi-photon tomography for 3D tracking of oligodendrocyte loss or single-cell sequencing to dissect glial cell responses.

In conclusion, this research provides a comprehensive characterisation of chronic IFN-α-driven WM pathology in a validated animal model. The findings reinforce the hypothesis that sustained IFN-α overexpression contributes to AGS progression through mechanisms involving vascular injury, neuroinflammation, and glial cell loss. The identified regional and age-dependent patterns offer insights into disease heterogeneity and potential therapeutic strategies, such as IFN-α inhibitors or myelin support therapies, which could mitigate WM degeneration in AGS patients. This model will be invaluable for preclinical testing of interventions targeting IFN-α pathways or downstream effectors in WM homeostasis.