IUF - Leibniz Research Institute for Environmental Medicine, Auf'm Hennekamp 50, 40225, Düsseldorf, Germany.
, Present address: Triskelion BV Utrechtseweg 48, 3704 HE, Zeist, The Netherlands.
Part Fibre Toxicol. 2017 Aug 30;14(1):35. doi: 10.1186/s12989-017-0213-5.
Increasing evidence from toxicological and epidemiological studies indicates that the central nervous system is an important target for ambient air pollutants. We have investigated whether long-term inhalation exposure to diesel engine exhaust (DEE), a dominant contributor to particulate air pollution in urban environments, can aggravate Alzheimer's Disease (AD)-like effects in female 5X Familial AD (5XFAD) mice and their wild-type female littermates. Following 3 and 13 weeks exposures to diluted DEE (0.95 mg/m, 6 h/day, 5 days/week) or clean air (controls) behaviour tests were performed and amyloid-β (Aβ) plaque formation, pulmonary histopathology and systemic inflammation were evaluated.
In a string suspension task, assessing for grip strength and motor coordination, 13 weeks exposed 5XFAD mice performed significantly less than the 5XFAD controls. Spatial working memory deficits, assessed by Y-maze and X-maze tasks, were not observed in association with the DEE exposures. Brains of the 3 weeks DEE-exposed 5XFAD mice showed significantly higher cortical Aβ plaque load and higher whole brain homogenate Aβ42 levels than the clean air-exposed 5XFAD littermate controls. After the 13 weeks exposures, with increasing age and progression of the AD-phenotype of the 5XFAD mice, DEE-related differences in amyloid pathology were no longer present. Immunohistochemical evaluation of lungs of the mice revealed no obvious genetic background-related differences in tissue structure, and the DEE exposure did not cause histopathological changes in the mice of both backgrounds. Luminex analysis of plasma cytokines demonstrated absence of sustained systemic inflammation upon DEE exposure.
Inhalation exposure to DEE causes accelerated plaque formation and motor function impairment in 5XFAD transgenic mice. Our study provides further support that the brain is a relevant target for the effects of inhaled DEE and suggests that long-term exposure to this ubiquitous air pollution mixture may promote the development of Alzheimer's disease.
越来越多的毒理学和流行病学研究证据表明，中枢神经系统是环境空气污染物的重要靶器官。我们研究了长期吸入柴油机排气（DEE）——城市环境中颗粒物空气污染的主要贡献者——是否会加重女性 5X 家族性 AD（5XFAD）小鼠及其野生型雌性同窝仔鼠的阿尔茨海默病（AD）样效应。在暴露于稀释的 DEE（0.95mg/m，6h/d，5d/wk）或清洁空气（对照）3 周和 13 周后，进行行为测试，并评估淀粉样β（Aβ）斑块形成、肺组织病理学和全身炎症。
在悬线任务中，评估抓握力和运动协调能力，13 周暴露的 5XFAD 小鼠的表现明显低于 5XFAD 对照小鼠。在 Y 迷宫和 X 迷宫任务中未观察到与 DEE 暴露相关的空间工作记忆缺陷。暴露于 3 周 DEE 的 5XFAD 小鼠的大脑皮质 Aβ斑块负荷明显高于清洁空气暴露的 5XFAD 同窝仔鼠对照，全脑匀浆 Aβ42 水平也明显升高。在 13 周暴露后，随着 5XFAD 小鼠 AD 表型的年龄增长和进展，与淀粉样蛋白病理学相关的 DEE 差异不再存在。对小鼠肺组织的免疫组织化学评价表明，组织结构无明显遗传背景相关差异，且 DEE 暴露未引起两种背景下的小鼠发生组织病理学改变。对血浆细胞因子的 Luminex 分析表明，DEE 暴露后无持续的全身炎症。
吸入 DEE 会导致 5XFAD 转基因小鼠斑块形成加速和运动功能障碍。我们的研究进一步支持大脑是吸入 DEE 作用的相关靶器官，并表明长期暴露于这种普遍存在的空气污染物混合物可能会促进阿尔茨海默病的发展。
