NADPH oxidase-mediated mitochondrial dysfunction contributes to high vulnerability of locus coeruleus noradrenergic neurons in response to inflammation Clinical evidence revealed that the loss of locus coeruleus noradrenergic (LC/NE) neurons is greater and occurs earlier than dopaminergic neurons in the substantia nigra (SN/DA) in Parkinsons disease (PD) patients. However, the mechanism remains unclear. The purpose of this study were: 1) to develop a rodent PD model displaying a temporal pattern of neurodegeneration that ascends caudo-rostrally from the lower brainstem to front cortex by a systemic injection of endotoxin, LPS; and 2) to elucidate mechanisms underlying the extreme vulnerability of NE/LC neurons during low-grade, chronic neuroinflammation. We found that LPS-injected mice displayed an ascending pattern of neurodegeneration similar to what found in PD brains: neuron loss started in NE/LC, followed by DA/SN, and finally in cortical and hippocampal regions. Mechanistic studies revealed that NE/LC neurons of normal mice exhibited higher degree of mitochondrial oxidative stress than neurons in other brain regions including DA/SN neurons, which was further elevated by LPS-induced neuroinflammation. Further studies showed that the activation of neuronal NADPH oxidase (NOX2) correlated with the degree of mitochondrial oxidative stress and subsequent dysfunction. We found that LPS treatment caused greater superoxide production and damage of mitochondria in NE/LC neurons than that of DA/SN neurons. These in vivo findings were further confirmed by in vitro studies showing that LPS activated neuronal NOX2, increased production of intracellular superoxide, suppressed ATP production and collapsed mitochondrial membrane potential in cultured neurons. Moreover, pharmacological inhibition or genetic ablation of NOX2 greatly attenuated LPS-induced mitochondrial dysfunction and afforded NE/LC neurons protection. Finally, this neuronal NOX2-mediated mitochondria dysfunction-based vulnerability of NE/LC neurons was further verified in a two-hit PD model generated by a single systemic LPS injection in transgenic mice over-expressing human A53T mutant -synuclein. In summary, our findings pointed to neuronal NOX2 activation and a resulting mitochondrial dysfunction as critical factors contributing to the extreme vulnerability of LC/NE neurons in PD.

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U.S. National Inst of Environ Hlth Scis
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