Astrocyte-specific deletion of ceruloplasmin exacerbates oxidative stress and demyelination in the spinal cord in a murine model of multiple sclerosis.

Abstract

Astrocytic iron metabolism is essential for maintaining central nervous system (CNS) homeostasis, particularly in the context of neurodegenerative and demyelinating disorders such as multiple sclerosis (MS). Disruption of this regulatory system can result in iron accumulation, heightened neuroinflammation, and demyelination, ultimately accelerating disease progression. Ceruloplasmin (Cp), a copper-containing ferroxidase enzyme highly expressed by astrocytes, plays a pivotal role in facilitating iron efflux and detoxification. However, the precise contribution of astrocytic Cp in demyelinating conditions is currently unknown. To investigate the role of astrocytic iron efflux and Cp in MS pathogenesis, we generated conditional knockout mice lacking Cp specifically in astrocytes (cKO) and induced experimental autoimmune encephalomyelitis (EAE), a widely accepted model of MS. cKO mice exhibited significantly worsened clinical outcomes, including earlier disease onset, increased peak severity, and higher cumulative disease scores during both acute and chronic phases. Histological analyses revealed enhanced microglial activation and lymphocyte infiltration in the spinal cord. These mice also showed elevated demyelination, oxidative stress, lipid peroxidation, and iron accumulation, particularly in spinal cord white matter regions. Similar pathological changes were observed in the cKO brain, with pronounced microglia activation, and immune cell infiltration particularly in the cerebellum. Collectively, these findings highlight a protective role for astrocytic Cp in mitigating neuroinflammation, oxidative damage, and demyelination during EAE. Elucidating the mechanisms by which astrocytic iron regulation influences MS progression may offer novel therapeutic targets focused on glial iron metabolism.