Neurodegenerative effects of air pollutant Particles: Biological mechanisms implicated for Early-Onset Alzheimer's disease

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.

Aim: 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, d_TEM = 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.

Keywords: Amyloid plaque; Diesel; Inflammation; Iron; Magnetite; Neurodegeneration; Oxidative stress; Particulate matter.