A2-astrocyte activation by short term hypoxia rescue α-synuclein preformed fibril induced neuronal cell death

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Abstract Parkinson’s disease (PD) is a neuro-degenerative disease for which a radical cure is not available, only symptomatic control. Studies have shown that hypoxia may have disease-modifying effects on PD. Herein, we investigated if short-term hypoxia activates astrocytes and if it has a protective effect on pre-formed fibril (PFF)-treated primary cortical neurones. Long-term hypoxia suppresses astrocyte activation and induces cell death, whereas short-term hypoxia activates astrocytes without affecting cellular apoptosis or viability. Short-term hypoxia restored cellular apoptosis and viability of PFF-treated neurones and reduced toxic phospho-α-synuclein (p-α-syn) aggregation. Similarly, short-term hypoxia-exposed astrocyte-conditioned medium rescued cellular apoptosis and viability of PFF-treated neurones and p-α-syn expression. Quantitative polymerase chain reaction revealed that short-term hypoxia promotes protective A2 astrocytes and suppresses toxic A1 astrocytes. Our findings suggest that short-term hypoxia has a neuro-protective effect against PD by activating protective A2 astrocytes, which rescue PFF-induced neuronal cell death. This provides insights into short-term hypoxia's clinical implications as a disease-modifying PD strategy.

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