aSyn aggregates induce microgliadependent neurotoxicity

Abstract

Parkinson’s disease (PD) is neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in substantia nigra pars compacta resulting in movement dysfunction. The main histological hallmark of PD is the presence of intracellular fibrillary aggregates, so-called Lewy bodies (LB). The formation of LB is considered the main cause of neuronal death in PD, but LB toxicity is currently under debate. Emerging evidence indicates that soluble aSyn oligomers are also toxic to neuronal cells. In addition, aSyn oligomers elevate in the extracellular space (cerebrospinal fluid) and are capable of spreading cell-tocell. Importantly, extracellular aSyn can affect both glial and neuronal cells. However, the interaction of brain cells under pathological conditions requires further investigation. Using rat neuronal-glial co-cultures, we found that pre-aggregated recombinant aSyn caused a gradual loss of neurons. Elimination of microglial cells abolished aSyn neurotoxicity, suggesting that microglial cells mediate neuronal loss. We also found that aSyn-induced neuronal loss was accompanied by the production of pro-inflammatory factors, such as nitric oxide and TNF-α. Overall, our results show that extracellular pre-aggregated aSyn induces microglia-dependent neurotoxicity in neuronal-glial co-cultures.