Abstract
IntroductionThe adult mammalian brain retains niches for neural stem cells (NSCs), which can generate glial and neuronal components of the brain tissue. However, it is barely established how chronic neuroinflammation, as it occurs in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, affects adult neurogenesis and, therefore, modulates the brain's potential for self-regeneration.MethodsNeural stem cell culture techniques, intraventricular tumor necrosis factor (TNF)-α infusion and the 6-hydroxydopamine mouse model were used to investigate the influence of neuroinflammation on adult neurogenesis in the Parkinson's disease background. Microscopic methods and behavioral tests were used to analyze samples.ResultsHere, we demonstrate that differences in the chronicity of TNF-α application to cultured NSCs result in opposed effects on their proliferation. However, chronic TNF-α treatment, mimicking Parkinson's disease associated neuroinflammation, shows detrimental effects on neural progenitor cell activity. Inversely, pharmacological inhibition of neuroinflammation in a 6-hydroxydopamine mouse model led to increased neural progenitor cell proliferation in the subventricular zone and neuroblast migration into the lesioned striatum. Four months after surgery, we measured improved Parkinson's disease-associated behavior, which was correlated with long-term anti-inflammatory treatment. But surprisingly, instead of newly generated striatal neurons, oligodendrogenesis in the striatum of treated mice was enhanced.ConclusionsWe conclude that anti-inflammatory treatment, in a 6-hydroxydopamine mouse model for Parkinson's disease, leads to activation of adult neural stem cells. These adult neural stem cells generate striatal oligodendrocytes. The higher numbers of newborn oligodendrocytes possibly contribute to axonal stability and function in this mouse model of Parkinson's disease and thereby attenuate dysfunctions of basalganglian motor-control.
Highlights
The adult mammalian brain retains niches for neural stem cells (NSCs), which can generate glial and neuronal components of the brain tissue
This is in line with most recent findings that show maintained levels of NSC proliferation in the subventricular zone (SVZ) of Parkinson’s disease (PD) patients [29], but in contrast to previous publications, which show a dependency of neural progenitor cell turn-over on dopaminergic innervations [30,31]
Our findings indicate that oligodendrocytes and oligodendrogenesis are important players in the pathology of Parkinson’s disease
Summary
The adult mammalian brain retains niches for neural stem cells (NSCs), which can generate glial and neuronal components of the brain tissue. It is barely established how chronic neuroinflammation, as it occurs in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, affects adult neurogenesis and, modulates the brain’s potential for self-regeneration. As a driving force for PD progression uncontrolled, chronic neuroinflammation has been described [2] It is under acute pathological situations, for example, after ischemic stroke, it has been shown that a fraction of these neuroblasts have the potential to migrate to the site of the lesion, where they differentiate into mature neurons [5,8].
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