Astrocytes in heavy metal neurotoxicity and neurodegeneration

Abstract

With the industrial development and progressive increase in environmental pollution, the mankind overexposure to heavy metals emerges as a pressing public health issue. Excessive intake of heavy metals, such as arsenic (As), manganese (Mn), mercury (Hg), aluminium (Al), lead (Pb), nickel (Ni), bismuth (Bi), cadmium (Cd), copper (Cu), zinc (Zn), and iron (Fe), is neurotoxic and it promotes neurodegeneration. Astrocytes are primary homeostatic cells in the central nervous system. They protect neurons against all types of insults, in particular by accumulating heavy metals. However, this makes astrocytes the main target for heavy metals neurotoxicity. Intake of heavy metals affects astroglial homeostatic and neuroprotective cascades including glutamate/GABA-glutamine shuttle, antioxidative machinery and energy metabolism. Deficits in these astroglial pathways facilitate or even instigate neurodegeneration. In this review, we provide a concise outlook on heavy metal-induced astrogliopathies and their association with major neurodegenerative disorders. In particular, we focus on astroglial mechanisms of iron-induced neurotoxicity. Iron deposits in the brain are detected in main neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Accumulation of iron in the brain is associated with motor and cognitive impairments and iron-induced histopathological manifestations may be considered as the potential diagnostic biomarker of neurodegenerative diseases. Effective management of heavy metal neurotoxicity can be regarded as a potential strategy to prevent or retard neurodegenerative pathologies.

Keywords: Astrocytes; Glutamate; Heavy metals; Neurodegeneration; Neurotoxicity.

Fig. 1.

3D-images of GFAP labelled astrocytes in frontal cortex. After treatment with dextran (control) or 2 mg/kg/day iron dextran for 6 days, 3D-images of GFAP residing in astrocytes were taken in the mouse frontal cortex indicating a development of reactive astrogliosis.

Fig. 2.

Excess iron aggravates malfunction of glymphatic system in chronic unpredictable mild stress-treated mice. (A, B) Mice were pre-treated with or without chronic unpredictable mild stress (CUMS) for 6 weeks; in the last week the mice were randomly separated to be injected with dextran or iron dextran for 6 days. The fluorescence tracer (OA555, 45 kDa) was injected intracisternally. (A) Representative images indicated the fluorescence tracer penetration into the brain; OA555 (red) and DAPI (blue; cell nuclei label) were stained simultaneously, in anterior and posterior brain slices. Scale bar, 1 mm. (B) Thirty minutes after injection, the animals were perfusion fixed and the whole-slice fluorescence was calculated. The fluorescence intensities of OA555 normalised to the intensity of the control group were assessed. Scale bar, 50 μm. Data are presented as mean ± SEM, n = 6. *p < 0.05, statistically significant difference compared to the control group. **p < 0.05, statistically significant difference compared to any other group (reproduced from Liang et al., 2020 with permission).