Increasing evidence from toxicological and epidemiological studies indicates that the brain is an important target for ambient (ultrafine) particles. Disturbance of redox-homeostasis and inflammation in the brain are proposed as possible mechanisms that can contribute to neurotoxic and neurodegenerative effects. Whether and how engineered nanoparticles (NPs) may cause neurotoxicity and promote neurodegenerative diseases such as Alzheimer's disease (AD) is largely unstudied.

We have assessed the neurological effects of subacute inhalation exposures (4 mg/m³ for 3 h/day, 5 days/week for 4 weeks) to cerium dioxide (CeO₂) NPs doped with different amounts of zirconium (Zr, 0%, 27% and 78%), to address the influence of particle redox-activity in the 5xFAD transgenic mouse model of AD. Four weeks post-exposure, effects on behaviour were evaluated and brain tissues were analysed for amyloid-β plaque formation and reactive microglia (Iba-1 staining). Behaviour was also evaluated in concurrently exposed non-transgenic C57BL/6J littermates, as well as in Western diet-fed apolipoprotein E-deficient (ApoE^-/-) mice as a model of vascular disease. Markers of inflammation and oxidative stress were evaluated in brain cortex.

The brains of the NP-exposed 5xFAD mice revealed no accelerated amyloid-β plaque formation. No significant treatment-related behaviour impairments were observed in the healthy C57BL/6J mice. In the 5xFAD and ApoE^-/- models, the NP inhalation exposures did not affect the alternation score in the X-maze indicating absence of spatial working memory deficits. However, following inhalation exposure to the 78% Zr-doped CeO₂ NPs changes in forced motor performance (string suspension) and exploratory motor activity (X-maze) were observed in ApoE^-/- and 5xFAD mice, respectively. Exposure to the 78% doped NPs also caused increased cortical expression of glial fibrillary acidic protein (GFAP) in the C57BL/6J mice. No significant treatment-related changes neuroinflammation and oxidative stress were observed in the 5xFAD and ApoE^-/- mice.

Our study findings reveal that subacute inhalation exposure to CeO₂ NPs does not accelerate the AD-like phenotype of the 5xFAD model. Further investigation is warranted to unravel whether the redox-activity dependent effects on motor activity as observed in the mouse models of AD and vascular disease result from specific neurotoxic effects of these NPs.

越来越多的毒理学和流行病学研究证据表明，大脑是环境（超细）颗粒的重要目标。大脑中氧化还原稳态的紊乱和炎症被认为是导致神经毒性和神经退行性影响的可能机制。工程纳米颗粒 (NP) 是否以及如何引起神经毒性并促进神经退行性疾病（如阿尔茨海默病 (AD)）在很大程度上尚未得到研究。

我们评估了亚急性吸入暴露（4 mg/m ^3，3小时/天，5 天/周，4 周）对_掺有不同量锆（Zr，0%， 27% 和 78%），以解决粒子氧化还原活性对 AD 的 5xFAD 转基因小鼠模型的影响。暴露后 4 周，评估对行为的影响，并分析脑组织的淀粉样蛋白-β 斑块形成​​和反应性小胶质细胞（Iba-1 染色）。行为也在同时暴露的非转基因 C57BL/6J 同窝小鼠以及西方饮食喂养的载脂蛋白 E 缺陷 (ApoE ^-/- ) 小鼠中作为血管疾病模型进行了评估。在大脑皮层中评估了炎症和氧化应激的标志物。

暴露于 NP 的 5xFAD 小鼠的大脑没有显示出加速的淀粉样蛋白-β 斑块形成​​。在健康的 C57BL/6J 小鼠中没有观察到明显的治疗相关行为障碍。在 5xFAD 和 ApoE ^-/-模型中，NP 吸入暴露不影响 X 迷宫中的交替得分，表明不存在空间工作记忆缺陷。然而，在吸入 78% Zr 掺杂的 CeO ₂ NPs 后，在 ApoE 中观察到强制运动性能（弦悬吊）和探索性运动活动（X 迷宫）的变化^-/-和 5xFAD 小鼠，分别。暴露于 78% 掺杂的 NPs 也会导致 C57BL/6J 小鼠皮质中神经胶质纤维酸性蛋白 (GFAP) 的表达增加。在 5xFAD 和 ApoE ^-/-小鼠中未观察到与治疗相关的神经炎症和氧化应激的显着变化。

我们的研究结果表明，亚急性吸入暴露于 CeO ₂ NPs 不会加速 5xFAD 模型的 AD 样表型。有必要进一步研究以阐明在 AD 和血管疾病小鼠模型中观察到的氧化还原活性依赖性对运动活动的影响是否是由这些 NP 的特定神经毒性作用引起的。