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<p>Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by degeneration of nigrostriatal dopaminergic neurons together with α-synuclein (α-syn) aggregation, neuroinflammation, and oxidative stress. Although intravenous immunoglobulin (IVIG) contains naturally occurring antibodies against α-syn oligomers, it has failed to demonstrate therapeutic efficacy in PD models, likely due to limited delivery across the blood–brain barrier (BBB). Enhancing BBB penetration of IVIG could therefore substantially improve its therapeutic potential in PD. Here, we developed a brain-targeted IVIG formulation (IVIGᴬ) by site-specifically conjugating Angiopep-2 (Ang-2) to the Fc glycan site (Asn297) of IVIG, enabling receptor-mediated transcytosis across the BBB via low-density lipoprotein receptor-related protein-1 (LRP1). Compared with unmodified IVIG, IVIGᴬ exhibited significantly enhanced brain accumulation. Moreover, systemic administration of IVIGᴬ markedly improved motor and cognitive performance in A53T α-syn transgenic mice by reducing phosphorylated α-syn aggregates, preserving dopaminergic neurons and synaptic integrity, and attenuating neuroinflammation, oxidative stress, and complement activation. These findings suggest that IVIGᴬ represents a promising immunotherapeutic agent with translational potential for the treatment of PD and other neurodegenerative disorders.</p> Graphical Abstract <p></p> <p>Fc-modified IVIG (IVIGᴬ) with enhanced blood brain barrier penetration reduces α-synuclein aggregation, improves neuronal survival and function, suppresses glia-mediated and complement-mediated inflammation, and ameliorates cognitive deficits and neuropathology in A53T α-synuclein transgenic mice.</p>

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Fc-Modified IVIG with Enhanced Blood–Brain Barrier Penetration Ameliorates Cognitive Deficits and Neuropathology in A53T α-Synuclein Transgenic Mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月14日

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  • Jie Zhu,
  • Ya-ru Huang,
  • Mei-qi Wang,
  • Shi-yu Liang,
  • Xiao-lin Yu,
  • Gui-feng Zhang,
  • Rui-tian Liu

摘要

Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by degeneration of nigrostriatal dopaminergic neurons together with α-synuclein (α-syn) aggregation, neuroinflammation, and oxidative stress. Although intravenous immunoglobulin (IVIG) contains naturally occurring antibodies against α-syn oligomers, it has failed to demonstrate therapeutic efficacy in PD models, likely due to limited delivery across the blood–brain barrier (BBB). Enhancing BBB penetration of IVIG could therefore substantially improve its therapeutic potential in PD. Here, we developed a brain-targeted IVIG formulation (IVIGᴬ) by site-specifically conjugating Angiopep-2 (Ang-2) to the Fc glycan site (Asn297) of IVIG, enabling receptor-mediated transcytosis across the BBB via low-density lipoprotein receptor-related protein-1 (LRP1). Compared with unmodified IVIG, IVIGᴬ exhibited significantly enhanced brain accumulation. Moreover, systemic administration of IVIGᴬ markedly improved motor and cognitive performance in A53T α-syn transgenic mice by reducing phosphorylated α-syn aggregates, preserving dopaminergic neurons and synaptic integrity, and attenuating neuroinflammation, oxidative stress, and complement activation. These findings suggest that IVIGᴬ represents a promising immunotherapeutic agent with translational potential for the treatment of PD and other neurodegenerative disorders.

Graphical Abstract

Fc-modified IVIG (IVIGᴬ) with enhanced blood brain barrier penetration reduces α-synuclein aggregation, improves neuronal survival and function, suppresses glia-mediated and complement-mediated inflammation, and ameliorates cognitive deficits and neuropathology in A53T α-synuclein transgenic mice.