Abstract
Neuroinflammation is potentiated by early degeneration of the locus coeruleus noradrenergic pathway (LC-NE) commonly seen in aging-related neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. In animal models, lipopolysaccharide (LPS) induces strong peripheral immune responses that can cause cognitive changes secondary to neuroinflammation. The influence of the peripheral immune response on cognition might be exacerbated by LC-NE degeneration, but this has not been well characterized previously. In this study, we investigated how systemic inflammation affects neuroinflammation and cognition in aged rats that have had either normal or damaged LC-NE transmitter systems. Rats were first exposed to the selective noradrenergic (NE) neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) to induce degeneration of central NE pathways. Two weeks later, the rats received a low dose of LPS. This resulted in 3 treatment groups (Control, LPS-, and DSP4+LPS-treated rats) studied at 4 hours (short-term subgroup) and 7 days (long-term subgroup) following the LPS injection. DSP4+LPS-treated rats exhibited increased serum levels of several pro-inflammatory cytokines, increased astroglial and microglial activation in the hippocampus, and poorer performance in the novel object recognition task (NORT) compared to controls and LPS-treated rats. Additionally, serum and brain tissue levels of brain-derived neurotrophic factor (BDNF) were modulated over time in the DSP4+LPS group compared to the other two groups. Specifically, DSP4+LPS-treated rats in the short-term subgroup had lower hippocampal BDNF levels (~25%) than controls and LPS-treated rats, which negatively correlated with hippocampal astrogliosis and positively correlated with hippocampal IL-1β levels. Serum and hippocampal BDNF levels in the DSP4+LPS-treated rats in the long-term subgroup returned to levels similar to the control group. These results show that systemic inflammation in LC-NE-lesioned aged rats promotes an exacerbated systemic and central inflammatory response compared to LC-NE-intact rats and alters BDNF levels, indicating the important role of this neurotransmitter system in response to neuroinflammation.
Highlights
Aging and aging-related disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by a subclinical chronic inflammatory status [1,2,3,4] and by increased pro-inflammatory markers in the brain [5]
Neuroinflammation induced by systemic inflammation has been implicated in the onset and progression of neurodegenerative diseases including AD, PD, and Down syndrome [2,3,4,10,59]
The results of the present study add to this literature and show that neuroinflammation induced by systemic inflammation is exacerbated by locus coeruleus noradrenergic pathway (LC-NE) lesion
Summary
Aging and aging-related disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by a subclinical chronic inflammatory status [1,2,3,4] and by increased pro-inflammatory markers in the brain [5]. Systemic inflammation induced by the bacterial endotoxin lipopolysaccharide (LPS) is welldocumented to cause neuroinflammation in animal models [9,10] despite the fact that the endotoxin does not readily cross the BBB [11,12]. Instead, circulating pro-inflammatory cytokines induced by systemic LPS cross the BBB, activate microglia, and directly inhibit crucial transcription factors in hippocampal neurons to induce neurodegeneration secondary to neuroinflammation [4,6,7,8,13,14]. Factors that further damage the BBB and increase its permeability, such as aging and noradrenergic degeneration [19,20], can exacerbate the detrimental neuronal effect of LPS-induced systemic inflammation
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