Viral inflammation, bioenergetics, and neurodegeneration

Abstract

The causes of most common neurodegenerative diseases (NDDs), like Alzheimer’s and Parkinson’s, remain largely unknown, however, neuroinflammation is considered an important pathophysiological factor that contributes to neuronal loss during NDDs. Emerging evidence suggests an association between prior viral infections and the onset of NDDs 1which highlights the potential causative link between viral neuroinflammation and neurodegeneration. Viral infections lead to the activation of innate immune cells of the brain – microglia, and prolonged activation results in a toxic environment which exacerbates neuronal damage and, in turn leads to further microglial activation fueling a vicious cycle of neuroinflammation. During bacterial inflammation changes in microglial inflammatory response are accompanied by changes in their energy metabolism involving the glycolytic system, TCA cycle and the OxPhos system2 , however not much is known about the effects of viral infection on the energy metabolism in microglia. Since the bioenergetic profile of immune cells is linked to their functional phenotype, it is important to know the impact of viral inflammation on the metabolism of microglial cells. We found that viral mimetics poly-(I:C) and loxoribine applied to primary neuronal-glial cultures induces loss of living neurons without increases in apoptosis or necrosis. Moreover, this loss of neurons was accompanied by microglial activation and increased phagocytic activity. In addition, we measured the impact of these viral mimetics on the mitochondrial respiration, glycolytic activity and amounts of certain TCA cycle-derived metabolites in a murine microglia cell line (BV-2) and found varying effects caused by these viral mimetics. In conclusion, we showed that viral inflammation can induce loss of neurons with concomitant microglial activation and it can also affect microglial energy metabolism.