Neurons survive interferonγ-primed microglial activation by high-dose LPS

Abstract

Regional differences in susceptibility to lipopolysaccharide(LPS)-induced neurodegeneration have been correlated to the relative abundance of microglia in rat brain in vitro and in vivo. On the other hand, high dose (1 µg/ml) LPS-induced activation of microglia-enriched primary cultures results in reduced microglial viability and release of proinflammatory factors. The aim of this study was to determine if over-activation-induced loss of microglia and reduced production of proinflammatory factors correlates with improved neuron survival in neuron/glia (M/G) mixed cultures. Mixed cultures of embryonic midbrain or cortical N/G were treated with both interferonγ and LPS and neurons and glia were assessed for function and survival. Over-activation of midbrain N/G by 1 µg/ml LPS correlated with greater dopamine uptake than that with 1ng/ml LPS. The midbrain N/G also showed reduced tumor necrosis factor α (TNFα) release but no change in nitric oxide (NO) production at high-dose LPS. With cortical N/G, LPS induced greater neurotoxicity at low-dose LPS than at the high dose. As in midbrain, the cortical N/G release of TNFα peaked at the lower dose of LPS yet was much less at high-dose LPS. NO production by cortical microglia was also less at high-dose LPS than the low dose. The number of OX-42 immunostained microglia was less after high-dose LPS than that after low-dose. The data suggest that over-activation of microglia in both midbrain N/G and cortical N/G culture systems correlates with loss of microglia and survival of neurons and support the idea that the number as well as functional status of microglia is central to LPS-induced neurodegeneration. Supported by NIEHS and Truman State University