Abstract
BackgroundChronic neurodegeneration results in microglial activation, but the contribution of inflammation to the progress of neurodegeneration remains unclear. We have shown that microglia express low levels of proinflammatory cytokines during chronic neurodegeneration but are “primed” to produce a more proinflammatory profile after systemic challenge with bacterial endotoxin (lipopolysaccharide [LPS]).MethodsHere, we investigated whether intraperitoneal (IP) challenge with LPS, to mimic systemic infection, in the early stages of prion disease can 1) produce exaggerated acute behavioral (n = 9) and central nervous system (CNS) inflammatory (n = 4) responses in diseased animals compared with control animals, and 2) whether a single LPS challenge can accelerate disease progression (n = 34–35).ResultsInjection of LPS (100 μg/kg), at 12 weeks postinoculation (PI), resulted in heightened CNS interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and interferon-beta (IFN-β) transcription and microglial IL-1β translation in prion-diseased animals relative to control animals. This inflammation caused exaggerated impairments in burrowing and locomotor activity, and induced hypothermia and cognitive changes in prion-diseased animals that were absent in LPS-treated control animals. At 15 weeks PI, LPS (500 μg/kg) acutely impaired motor coordination and muscle strength in prion-diseased but not in control animals. After recovery, these animals also showed earlier onset of disease-associated impairments on these parameters.ConclusionsThese data demonstrate that transient systemic inflammation superimposed on neurodegenerative disease acutely exacerbates cognitive and motor symptoms of disease and accelerates disease progression. These deleterious effects of systemic inflammation have implications for the treatment of chronic neurodegeneration and associated delirium.
Highlights
Chronic neurodegeneration results in microglial activation, but the contribution of inflammation to the progress of neurodegeneration remains unclear
Here, we investigated whether intraperitoneal (IP) challenge with LPS, to mimic systemic infection, in the early stages of prion disease can 1) produce exaggerated acute behavioral (n ϭ 9) and central nervous system (CNS) inflammatory (n ϭ 4) responses in diseased animals compared with control animals, and 2) whether a single LPS challenge can accelerate disease progression (n ϭ 34 –35)
At 15 weeks PI, LPS (500 g/kg) acutely impaired motor coordination and muscle strength in prion-diseased but not in control animals. These animals showed earlier onset of disease-associated impairments on these parameters. These data demonstrate that transient systemic inflammation superimposed on neurodegenerative disease acutely exacerbates cognitive and motor symptoms of disease and accelerates disease progression
Summary
We investigated whether intraperitoneal (IP) challenge with LPS, to mimic systemic infection, in the early stages of prion disease can 1) produce exaggerated acute behavioral (n ϭ 9) and central nervous system (CNS) inflammatory (n ϭ 4) responses in diseased animals compared with control animals, and 2) whether a single LPS challenge can accelerate disease progression (n ϭ 34 –35). Animals and Stereotaxic Surgery Female C57BL/6 mice, n ϭ 233 (Harlan Olac, United Kingdom), were housed in cages of five at 21°C with a 12:12 hour light-dark cycle (lights on 0700 to 1900) with free access to food and water. They were anesthetized intraperitoneally (IP) with Avertin (Sigma, Poole, United Kingdom) and positioned in a stereotaxic frame. Further animals (n ϭ 9) were injected intracerebrally (IC) with N-methyl-D-aspartate (NMDA) (10 mg/mL) to ablate the hippocampus This surgery was performed under isoflurane anesthesia (approximately 2%) with perisurgical analgesia (carprophen, 5 mg/kg). Female animals were used for all studies to minimize the occurrence of fighting, since this has significant effects on behavior
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