Role of IGF2 on inflammatory response in Parkinson's models

Abstract

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra, leading to motor deficits. α-Synuclein (α-syn) aggregates and neuroinflammation are hallmarks of PD, but the underlying molecular mechanisms remain unclear. This study investigated the involvement of IGF2 in the modulating of inflammation and neuroprotection in preclinical PD models. Analysis of PD patient samples and a preclinical model revealed dysregulated IGF2 levels, increased proinflammatory cytokines, and activation of Toll-like receptor 4 (TLR4)-mediated inflammatory pathways. Remarkably, IGF2 treatment demonstrated significant anti-inflammatory effects in macrophages exposed to α-syn preformed fibrils (PFF), suppressing proinflammatory cytokine production and TLR4 signaling. Moreover, IGF2 protected dopaminergic neurons against α-syn aggregates, highlighting its neuroprotective potential. Additionally, treatment with IGF2-preconditioned macrophages (MIGF2) reduced the inflammatory profile in peripheral mononuclear cells (PBMCs) and neuroinflammation in central nervous system. Notably, MIGF2 treatment improved motor performance, reduced α-syn accumulation in the substantia nigra, and prevent dopaminergic neuronal loss. Overall, our findings highlight the crucial role of IGF2 in modulating inflammation in PD. Dysregulation of IGF2 levels may contribute to neuroinflammatory processes underlying of the PD progression. By attenuating inflammation and protecting dopaminergic neurons, IGF2 emerges as a potential therapeutic target for PD.

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra, leading to motor deficits. α-Synuclein (α-syn) aggregates and neuroinflammation are hallmarks of PD, but the underlying molecular mechanisms remain unclear. This study investigated the involvement of IGF2 in the modulating of inflammation and neuroprotection in preclinical PD models. Analysis of PD patient samples and a preclinical model revealed dysregulated IGF2 levels, increased proinflammatory cytokines, and activation of Toll-like receptor 4 (TLR4)-mediated inflammatory pathways. Remarkably, IGF2 treatment demonstrated significant anti-inflammatory effects in macrophages exposed to α-syn preformed fibrils (PFF), suppressing proinflammatory cytokine production and TLR4 signaling. Moreover, IGF2 protected dopaminergic neurons against α-syn aggregates, highlighting its neuroprotective potential. Additionally, treatment with IGF2-preconditioned macrophages (MIGF2) reduced the inflammatory profile in peripheral mononuclear cells (PBMCs) and neuroinflammation in central nervous system. Notably, MIGF2 treatment improved motor performance, reduced α-syn accumulation in the substantia nigra, and prevent dopaminergic neuronal loss. Overall, our findings highlight the crucial role of IGF2 in modulating inflammation in PD. Dysregulation of IGF2 levels may contribute to neuroinflammatory processes underlying of the PD progression. By attenuating inflammation and protecting dopaminergic neurons, IGF2 emerges as a potential therapeutic target for PD.