Abstract：
BACKGROUND: Sporadic Alzheimer\'s disease (AD) occurs in 99% of all cases and can be influenced by air pollution such as diesel emissions and more recently, an iron oxide particle, magnetite, detected in the brains of AD patients. However, a mechanistic link between air pollutants and AD development remains elusive.
OBJECTIVE: To study the development of AD-relevant pathological effects induced by air pollutant particle exposures and their mechanistic links, in wild-type and AD-predisposed models.
METHODS: C57BL/6 (n = 37) and APP/PS1 transgenic (n = 38) mice (age 13 weeks) were exposed to model pollutant iron-based particle (Fe0-Fe3O4, dTEM = 493 ± 133 nm), hydrocarbon-based diesel combustion particle (43 ± 9 nm) and magnetite (Fe3O4, 153 ± 43 nm) particles (66 µg/20 µL/third day) for 4 months, and were assessed for behavioural changes, neuronal cell loss, amyloid-beta (Aβ) plaque, immune response and oxidative stress-biomarkers. Neuroblastoma SHSY5Y (differentiated) cells were exposed to the particles (100 μg/ml) for 24 h, with assessments on immune response biomarkers and reactive oxygen species generation.
RESULTS: Pollutant particle-exposure led to increased anxiety and stress levels in wild-type mice and short-term memory impairment in AD-prone mice. Neuronal cell loss was shown in the hippocampal and somatosensory cortex, with increased detection of Aβ plaque, the latter only in the AD-predisposed mice, with the wild-type not genetically disposed to form the plaque. The particle exposures however, increased AD-relevant immune system responses, including inflammation, in both strains of mice. Exposures also stimulated oxidative stress, although only observed in wild-type mice. The in vitro studies complemented the immune response and oxidative stress observations.
CONCLUSIONS: This study provides insights into the mechanistic links between inflammation and oxidative stress to pollutant particle-induced AD pathologies, with magnetite apparently inducing the most pathological effects. No exacerbation of the effects was observed in the AD-predisposed model when compared to the wild-type, indicating a particle-induced neurodegeneration that is independent of disease state.
OBJECTIVE: To study the development of AD-relevant pathological effects induced by air pollutant particle exposures and their mechanistic links, in wild-type and AD-predisposed models.
METHODS: C57BL/6 (n = 37) and APP/PS1 transgenic (n = 38) mice (age 13 weeks) were exposed to model pollutant iron-based particle (Fe0-Fe3O4, dTEM = 493 ± 133 nm), hydrocarbon-based diesel combustion particle (43 ± 9 nm) and magnetite (Fe3O4, 153 ± 43 nm) particles (66 µg/20 µL/third day) for 4 months, and were assessed for behavioural changes, neuronal cell loss, amyloid-beta (Aβ) plaque, immune response and oxidative stress-biomarkers. Neuroblastoma SHSY5Y (differentiated) cells were exposed to the particles (100 μg/ml) for 24 h, with assessments on immune response biomarkers and reactive oxygen species generation.
RESULTS: Pollutant particle-exposure led to increased anxiety and stress levels in wild-type mice and short-term memory impairment in AD-prone mice. Neuronal cell loss was shown in the hippocampal and somatosensory cortex, with increased detection of Aβ plaque, the latter only in the AD-predisposed mice, with the wild-type not genetically disposed to form the plaque. The particle exposures however, increased AD-relevant immune system responses, including inflammation, in both strains of mice. Exposures also stimulated oxidative stress, although only observed in wild-type mice. The in vitro studies complemented the immune response and oxidative stress observations.
CONCLUSIONS: This study provides insights into the mechanistic links between inflammation and oxidative stress to pollutant particle-induced AD pathologies, with magnetite apparently inducing the most pathological effects. No exacerbation of the effects was observed in the AD-predisposed model when compared to the wild-type, indicating a particle-induced neurodegeneration that is independent of disease state.
摘要：
背景：散发性阿尔茨海默病（AD）发生在所有病例的99％中，并且可能受到柴油排放等空气污染的影响，最近，氧化铁颗粒，磁铁矿,在AD患者的大脑中检测到。然而,空气污染物与AD发展之间的机械联系仍然难以捉摸。
目的：研究空气污染物颗粒暴露引起的AD相关病理效应的发展及其机制联系，在野生型和AD易感模型中。
方法：将C57BL/6（n=37）和APP/PS1转基因（n=38）小鼠（13周龄）暴露于模型污染物铁基颗粒（Fe0-Fe3O4，dTEM=493±133nm），烃类柴油燃烧颗粒（43±9nm）和磁铁矿（Fe3O4，153±43nm）颗粒（66µg/20µL/第三天），持续4个月，并评估了行为变化，神经元细胞丢失，淀粉样β（Aβ）斑块，免疫反应和氧化应激生物标志物。将神经母细胞瘤SHSY5Y（分化）细胞暴露于颗粒（100μg/ml）24小时，评估免疫反应生物标志物和活性氧的产生。
结果：污染物颗粒暴露导致野生型小鼠的焦虑和压力水平增加，AD易感小鼠的短期记忆障碍。神经元细胞丢失显示在海马和体感皮层，随着Aβ斑块检测的增加，后者仅在AD易感小鼠中，野生型没有遗传上形成斑块。然而，粒子暴露，增加与AD相关的免疫系统反应，包括炎症,在这两种小鼠中。暴露也刺激了氧化应激，尽管仅在野生型小鼠中观察到。体外研究补充了免疫应答和氧化应激观察。
结论：这项研究提供了对炎症和氧化应激与污染物颗粒诱导的AD病理之间的机制联系的见解，磁铁矿显然诱发了最多的病理效应。与野生型相比，在AD易感模型中未观察到效应的恶化。表明颗粒诱导的神经变性与疾病状态无关。
目的：研究空气污染物颗粒暴露引起的AD相关病理效应的发展及其机制联系，在野生型和AD易感模型中。
方法：将C57BL/6（n=37）和APP/PS1转基因（n=38）小鼠（13周龄）暴露于模型污染物铁基颗粒（Fe0-Fe3O4，dTEM=493±133nm），烃类柴油燃烧颗粒（43±9nm）和磁铁矿（Fe3O4，153±43nm）颗粒（66µg/20µL/第三天），持续4个月，并评估了行为变化，神经元细胞丢失，淀粉样β（Aβ）斑块，免疫反应和氧化应激生物标志物。将神经母细胞瘤SHSY5Y（分化）细胞暴露于颗粒（100μg/ml）24小时，评估免疫反应生物标志物和活性氧的产生。
结果：污染物颗粒暴露导致野生型小鼠的焦虑和压力水平增加，AD易感小鼠的短期记忆障碍。神经元细胞丢失显示在海马和体感皮层，随着Aβ斑块检测的增加，后者仅在AD易感小鼠中，野生型没有遗传上形成斑块。然而，粒子暴露，增加与AD相关的免疫系统反应，包括炎症,在这两种小鼠中。暴露也刺激了氧化应激，尽管仅在野生型小鼠中观察到。体外研究补充了免疫应答和氧化应激观察。
结论：这项研究提供了对炎症和氧化应激与污染物颗粒诱导的AD病理之间的机制联系的见解，磁铁矿显然诱发了最多的病理效应。与野生型相比，在AD易感模型中未观察到效应的恶化。表明颗粒诱导的神经变性与疾病状态无关。
