Regional Distributions of Iron, Copper and Zinc and Their Relationships With Glia in a Normal Aging Mouse Model

Abstract

Microglia and astrocytes can quench metal toxicity to maintain tissue homeostasis, but with age, increasing glial dystrophy alongside metal dyshomeostasis may predispose the aged brain to acquire neurodegenerative diseases. The aim of the present study was to investigate age-related changes in brain metal deposition along with glial distribution in normal C57Bl/6J mice aged 2-, 6-, 19-and 27-months (n = 4/age). Using synchrotronbased X-ray fluorescence elemental mapping, we demonstrated age-related increases in iron, copper, and zinc in the basal ganglia (p < 0.05). Qualitative assessments revealed age-associated increases in iron, particularly in the basal ganglia and zinc in the white matter tracts, while copper showed overt enrichment in the choroid plexus/ventricles. Immunohistochemical staining showed augmented numbers of microglia and astrocytes, as a function of aging, in the basal ganglia (p < 0.05). Moreover, qualitative analysis of the glial immunostaining at the level of the fimbria and ventral commissure, revealed increments in the number of microglia but decrements in astroglia, in older aged mice. Upon morphological evaluation, aged microglia and astroglia displayed enlarged soma and thickened processes, reminiscent of dystrophy. Since glial cells have major roles in metal metabolism, we performed linear regression analysis and found a positive association between iron (R 2 = 0.57, p = 0.0008), copper (R 2 = 0.43, p = 0.0057), and zinc (R 2 = 0.37, p = 0.0132) with microglia in the basal ganglia. Also, higher levels of iron (R 2 = 0.49, p = 0.0025) and zinc (R 2 = 0.27, p = 0.040) were correlated to higher astroglia numbers. Aging was accompanied by a dissociation between metal and glial levels, as we found through the formulation of metal to glia ratios, with regions of basal ganglia being differentially affected. For example, iron to astroglia ratio showed age-related increases in the substantia nigra and globus pallidus, while the ratio was decreased in the striatum. Meanwhile, copper and zinc to astroglia ratios showed a similar regional decline. Our findings suggest that inflammation at the choroid plexus,

Ferroptosis Is Regulated by Mitochondria in Neurodegenerative Diseases

“…Reduced ceruloplasmin activity in PD can cause lipid peroxidation and neurodegeneration in the SN by inducing iron accumulation [92]. In addition, a dissociation between iron accumulation and ferritin upregulation was observed in the aged SN previously, and it was found that higher levels of iron were not associated with increased levels of ferritin [95]. There are also studies showing that ferritin levels in the SN of PD patients are decreased, and H-ferritin and L-ferritin have been reported to be 75 and 37% of normal values, thus making neurons susceptible to iron-induced oxidative damage [96].…”

Zinc Therapy in Early Alzheimer’s Disease: Safety and Potential Therapeutic Efficacy

“…Labile trace elements concentrations in different brain regions, otherwise meticulously maintained within narrow limits, are deregulated upon aging and inflammation at the choroid plexus due to perturbed BBB [22], and further increase during AD course (reviewed in [11,12]). Astrocytes and microglia both confer protection by scavenging metals that cross BBB, thereby protecting neurons by attenuating neural excitotoxicity [23].…”

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