PD MODEL USING IPSC-DERIVED AGED ASTROCYTES REVEALS INDUCTION OF NEUROTOXICITY BY STIMULATION WITH Α-SYNUCLEIN AND IFN-Γ

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra. Previous epidemiological studies have demonstrated that aging is involved in the development of PD, and it is widely recognized as a major risk factor for the disease. The aggregation and accumulation of α-synuclein protein are considered to play a key role in the pathogenesis of PD. Additionally, it has been reported that astrocytes, which normally protect neurons, transform into a neurotoxic state in PD patients. In this study, we generated aged astrocytes derived from human induced pluripotent stem cells (iPSCs) and evaluated the relationship between α-synuclein and neurotoxicity.
The aged astrocytes derived from human iPSCs exhibited increased expression of senescence markers, including CDKN2A, SA-β-Gal, and γH2AX. We found that stimulation of human aged astrocytes with TNF-α and IFN-γ induces a neurotoxic phenotype. Subsequently, we evaluated the neurotoxicity of aged astrocytes stimulated with various forms of α-synuclein. As a result, we found that in the presence of microglia, stimulation of aged astrocytes with α-synuclein PFF and IFN-γ induced neurotoxicity. Furthermore, we demonstrated that Toll-like receptors are involved in the mechanism of neurotoxic induction.
In our study, we successfully recapitulated α-synuclein-induced neurotoxic phenotype by utilizing aged astrocytes. These findings can contribute to the development of new therapeutic agents and further understanding of PD pathology.