Systemic Inflammation Induces Acute Behavioral and Cognitive Changes and Accelerates Neurodegenerative Disease

炎症 疾病 认知 神经科学 全身炎症 医学 认知功能衰退 心理学 免疫学 痴呆 病理
作者
Colm Cunningham,Suzanne Campion,Katie Lunnon,Carol Murray,Jack Woods,Robert M. J. Deacon,J. N. P. Rawlins,V. Hugh Perry
出处
期刊:Biological Psychiatry [Elsevier]
卷期号:65 (4): 304-312 被引量:550
标识
DOI:10.1016/j.biopsych.2008.07.024
摘要

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. Chronic 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]). 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 = 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). Injection 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. These 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.

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