Long-term effects of LPS and high-fat diet on dopaminergic neurodegeneration

Date

2013

Authors

Stojakovic, Andrea

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Abstract

Mounting evidence suggests that inflammation is involved in the etiology of neurodegenerative disorders such as Parkinson's disease. It has been reported that the long-term effect of five doses of lipopolysaccharide from Gram-negative bacteria in mice caused activation of microglia and dopaminergic neurodegeneration that was reflected as decreased locomotor activity. In the current study, it is hypothesized that IL-1 beta, a potent proinflammatory cytokine synthesized and released by glia cells, could be mediating the LPS-induced dopaminergic neurodegeneration and that the chronic low-grade inflammatory state caused by diet-induced obesity would exacerbate LPS-induced neurodegeneration. To ascertain the participation of IL-1 beta, three strains of mice were employed: a control [wild type (WT)], a strain lacking the endogenous antagonist of IL-1, namely IL-1 receptor antagonist (IL-1ra-/-), and a mouse strain deficient in caspase-1 (Casp-1-/-), a protease that cleaves the immature IL-1 beta into the mature, biologically active form. Mice of the three genotypes were fed a regular diet (RD) and additionally WT mice were fed a high-fat diet (HFD). All mouse groups were challenged with intraperitoneal injections of either saline or LPS (5 mg/kg; one or five times on a monthly basis). Significant genotype and diet effects were observed in behavioral, metabolic and inflammatory outcomes over a period of 9 to 15 months, whereas the effect of LPS was modest or undetectable. Compared to WT mice, Casp-1-/- mice preserved their locomotor activities, while IL-1ra-/- mice showed a time-dependent decline in motor and coordinative abilities. Non-motor symptoms included age-related development of anxiety-like behavior in IL-1ra-/- mice. Impairment of cognitive function was observed in Casp-1-/- mice. Since insulin and leptin may modulate dopamine neurotransmission, plasma levels of these two hormones were assessed. Casp-1-/- mice had increased plasma insulin levels but were not glucose intolerant, whereas IL-1ra-/- mice were hypoinsulinemic, but insulin sensitive. Leptin levels were reduced in both genotypes (Casp-1-/- and IL-1ra-/-). Casp-1-/- mice had intact dopamine neurons and less activated microglia cells. Dopamine neurodegeneration was observed in IL-1ra-/- mice and accompanied by higher, but non-significant activation of microglia. The connection between peripheral and central inflammation was assessed by plasma level of monocyte chemoattractant protein-1 (MCP-1). Plasma MCP-1 tended to be increased by repeated LPS injections in WT mice and surprisingly it was reduced by single and repeated LPS injections in both Casp-1-/- and IL-1ra-/- mice. Significant differences in final outcomes were observed between the two diet-fed groups of mice. LPS treatments did not induce motor decline in RD and HFD-fed mice during nine months of experiments. However, HFD mice showed symptoms of akinesia, bradykinesia, dyskinesia and reduced coordinative abilities. Non-motor symptoms observed in HFD mice were anxiety-like behavior in novelty suppressed feeding test, cognitive and partial memory impairment. HFD mice displayed glucose intolerance, high levels of leptin and insulin. Dopamine neurons were not affected by HFD and significant decreases were induced by repeated LPS injections. Loss of neurons was not accompanied with increased activation of microglia cells and MCP-1. Overall, the data shown here emphasized the importance of the IL-1 signaling pathway in dopaminergic neurodegeneration.

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Thesis (PhD)

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DOI

10.25911/5d514c345319c

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