Abstract
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.
Highlights
Several research groups have postulated that ultrafine air pollution particles are an important environmental risk factor for neurotoxicity and, may potentiate the risk of neurodegenerative disorders, like Alzheimer’s Disease (AD) (reviewed in (Heusinkveld et al 2016)
Given that free radicals play a prominent role in the pathology of many neurological diseases, we explored the neurotoxicity of CeO2 NPs doped with varying amounts of Zr following inhalation exposure in three different mouse models, i.e. C57BL/6J, 5xFAD and ApoE-/- mice
The 5xFAD mouse model was used in a previous study, in which we have demonstrated that inhalation exposure to diesel engine exhaust results in an accelerated formation of Aβ-plaques as well as motor function impairment (Hullmann et al 2017)
Summary
Several research groups have postulated that ultrafine air pollution particles are an important environmental risk factor for neurotoxicity and, may potentiate the risk of neurodegenerative disorders, like Alzheimer’s Disease (AD) (reviewed in (Heusinkveld et al 2016). Concerns have been raised about the potential neurotoxic and neurodegenerative effects of engineered nanoparticles (NPs). Despite great progress in nanotechnologies, comparatively little is known to date on the potential adverse effects that exposure to manufactured NPs may have on the human brain, including the potential induction of pathways leading to neurodegeneration (Cupaioli et al 2014). NPs can enter the human body through several routes, e.g. via inhalation, absorption from the digestive tract, or following injection into the blood in nanomedical applications. With regard to potential adverse impacts on the brain, uptake and retrograde axonal transport of NPs via the olfactory nerve has been demonstrated in rodent inhalation studies (Oberdorster et al 2004; Elder et al 2006; Elder and Oberdorster 2006). Oxidative stress and neuroinflammation have long been recognised in neurotoxicity and neurodegenerative diseases including AD (Heneka et al 2015; Zhao and Zhao 2013)
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