年龄相关性认知障碍与发作性全身炎症小鼠模型中的长期神经炎症和氧化应激有关。
Age-related cognitive impairment is associated with long-term neuroinflammation and oxidative stress in a mouse model of episodic systemic inflammation.
机构信息
Laboratory of Immunopharmacology, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.
Institute of Medical Biochemistry Leopoldo DeMeis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
出版信息
J Neuroinflammation. 2018 Jan 30;15(1):28. doi: 10.1186/s12974-018-1059-y.
BACKGROUND
Microglia function is essential to maintain the brain homeostasis. Evidence shows that aged microglia are primed and show exaggerated response to acute inflammatory challenge. Systemic inflammation signals to the brain inducing changes that impact cognitive function. However, the mechanisms involved in age-related cognitive decline associated to episodic systemic inflammation are not completely understood. The aim of this study was to identify neuropathological features associated to age-related cognitive decline in a mouse model of episodic systemic inflammation.
METHODS
Young and aged Swiss mice were injected with low doses of LPS once a week for 6 weeks to induce episodic systemic inflammation. Sickness behavior, inflammatory markers, and neuroinflammation were assessed in different phases of systemic inflammation in young and aged mice. Behavior was evaluated long term after episodic systemic inflammation by open field, forced swimming, object recognition, and water maze tests.
RESULTS
Episodic systemic inflammation induced systemic inflammation and sickness behavior mainly in aged mice. Systemic inflammation induced depressive-like behavior in both young and aged mice. Memory and learning were significantly affected in aged mice that presented lower exploratory activity and deficits in episodic and spatial memories, compared to aged controls and to young after episodic systemic inflammation. Systemic inflammation induced acute microglia activation in young mice that returned to base levels long term after episodic systemic inflammation. Aged mice presented dystrophic microglia in the hippocampus and entorhinal cortex at basal level and did not change morphology in the acute response to SI. Regardless of their dystrophic microglia, aged mice produced higher levels of pro-inflammatory (IL-1β and IL-6) as well as pro-resolution (IL-10 and IL-4) cytokines in the brain. Also, higher levels of Nox2 expression, oxidized proteins and lower antioxidant defenses were found in the aged brains compared to the young after episodic systemic inflammation.
CONCLUSIONS
Our data show that aged mice have increased susceptibility to episodic systemic inflammation. Aged mice that showed cognitive impairments also presented higher oxidative stress and abnormal production of cytokines in their brains. These results indicate that a neuroinflammation and oxidative stress are pathophysiological mechanisms of age-related cognitive impairments.
背景
小胶质细胞的功能对于维持大脑内环境稳定至关重要。有证据表明，衰老的小胶质细胞被预先激活，并对急性炎症挑战表现出过度反应。全身炎症信号传递到大脑，引起影响认知功能的变化。然而，与 episodic 全身炎症相关的与年龄相关的认知能力下降的机制尚不完全清楚。本研究旨在确定与 episodic 全身炎症相关的与年龄相关的认知能力下降相关的神经病理学特征。
方法
年轻和年老的瑞士小鼠每周接受低剂量 LPS 注射一次，持续 6 周，以诱导 episodic 全身炎症。在年轻和年老小鼠的全身炎症的不同阶段评估疾病行为、炎症标志物和神经炎症。 episodic 全身炎症后通过旷场、强迫游泳、物体识别和水迷宫测试长期评估行为。
结果
episodic 全身炎症主要在年老小鼠中诱导全身炎症和疾病行为。全身炎症在年轻和年老小鼠中均诱导抑郁样行为。记忆和学习在年老小鼠中受到显著影响，与年老对照组和 episodic 全身炎症后的年轻小鼠相比，年老小鼠的探索性活动减少， episodic 和空间记忆受损。 episodic 全身炎症诱导年轻小鼠急性小胶质细胞激活，长期后 episodic 全身炎症后恢复至基础水平。年老小鼠在基础水平上即存在海马和内嗅皮层的退行性小胶质细胞，并且在急性全身炎症反应中形态没有改变。无论退行性小胶质细胞如何，年老小鼠在大脑中产生更高水平的促炎（IL-1β 和 IL-6）和促分解（IL-10 和 IL-4）细胞因子。 episodic 全身炎症后，与年轻小鼠相比，年老小鼠的大脑中还发现了更高水平的 Nox2 表达、氧化蛋白和较低的抗氧化防御。
结论
我们的数据表明，年老小鼠对 episodic 全身炎症更敏感。表现出认知障碍的年老小鼠的大脑中也存在更高的氧化应激和异常细胞因子产生。这些结果表明，神经炎症和氧化应激是与年龄相关的认知障碍的病理生理机制。
Zotero 插件