Parkinson's disease (PD) develops over decades through spatiotemporal stages that ascend from the brainstem to the forebrain. The mechanism behind this caudo-rostral neurodegeneration remains largely undefined. In unraveling this phenomenon,… Click to show full abstract
Parkinson's disease (PD) develops over decades through spatiotemporal stages that ascend from the brainstem to the forebrain. The mechanism behind this caudo-rostral neurodegeneration remains largely undefined. In unraveling this phenomenon, we recently developed a lipopolysaccharide (LPS)-elicited chronic neuroinflammatory mouse model that displays sequential losses of neurons in brainstem, substantia nigra, hippocampus and cortex. In this study, we aimed to investigate the mechanisms of caudo-rostral neurodegeneration and focused our efforts on the earliest neurodegeneration of vulnerable noradrenergic locus coeruleus (NE-LC) neurons in the brainstem. We found that compared with neurons in other brain regions, NE-LC neurons in untreated mice displayed high levels of mitochondrial oxidative stress that was severely exacerbated in the presence of LPS-elicited chronic neuroinflammation. In agreement, NE-LC neurons in LPS-treated mice displayed early reduction of complex IV expression and mitochondrial swelling and loss of cristae. Mechanistically, the activation of the superoxide-generating enzyme NADPH oxidase (NOX2) on NE-LC neurons was essential for their heightened vulnerability during chronic neuroinflammation. LPS induced early and high expressions of NOX2 in NE-LC neurons. Genetic or pharmacological inactivation of NOX2 markedly reduced mitochondrial oxidative stress and dysfunction in LPS-treated mice. Furthermore, inhibition of NOX2 significantly ameliorated LPS-induced NE-LC neurodegeneration. More importantly, post-treatment with NOX2 inhibitor diphenyleneiodonium when NE-LC neurodegeneration had already begun, still showed high efficacy in protecting NE-LC neurons from degeneration in LPS-treated mice. This study strongly supports that chronic neuroinflammation and NOX2 expression among vulnerable neuronal populations contribute to caudo-rostral degeneration in PD.
               
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