Age-related accumulation of toxic metals in the human locus ceruleus.

Roger Pamphlett,Philip A Doble,David P Bishop,Stephen Kum Jew

doi:10.1371/journal.pone.0203627

Roger Pamphlett, Philip A Doble + Show 2 more

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https://doi.org/10.1371/journal.pone.0203627

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Abstract

Damage to the locus ceruleus has been implicated in the pathogenesis of a number of neurological conditions. Locus ceruleus neurons accumulate toxic metals such as mercury selectively, however, the presence of toxic metals in locus ceruleus neurons of people of different ages, and with a variety of disorders, is not known. To demonstrate at what age toxic metals are first detectable in the locus ceruleus, and to evaluate whether their presence is more common in certain clinicopathological conditions, we looked for these metals in 228 locus ceruleus samples. Samples were taken at coronial autopsies from individuals with a wide range of ages, pre-existing conditions and causes of death. Paraffin sections of pons containing the locus ceruleus were stained with silver nitrate autometallography, which indicates inorganic mercury, silver and bismuth within cells (termed autometallography-detected toxic metals, or AMG™). No locus ceruleus AMG neurons were seen in 38 individuals aged under 20 years. 47% of the 190 adults (ie, aged 20 years and over) had AMG locus ceruleus neurons. The proportion of adults with locus ceruleus AMG neurons increased during aging, except for a decreased proportion in the 90-plus years age group. No differences were found in the proportions of locus ceruleus AMG neurons between groups with different neurological, psychiatric, or other clinicopathological conditions, or among various causes of death. Elemental analysis with laser ablation-inductively coupled plasma-mass spectrometry was used to cross-validate the metals detected by AMG, by looking for silver, gold, bismuth, cadmium, chromium, iron, mercury, nickel, and lead in the locus ceruleus of ten individuals. This confirmed the presence of mercury in locus ceruleus samples containing AMG neurons, and showed cadmium, silver, lead, iron, and nickel in the locus ceruleus of some individuals. In conclusion, toxic metals stained by AMG (most likely inorganic mercury) appear in locus ceruleus neurons in early adult life. About half of adults in this study had locus ceruleus neurons containing inorganic mercury, and elemental analysis found a range of other toxic metals in the locus ceruleus. Locus ceruleus inorganic mercury increased during aging, except for a decrease in advanced age, but was not found more often in any single clinicopathological condition or cause of death.

Highlights

The locus ceruleus supplies noradrenaline to the central nervous system, by which it influences neuronal and glial function and maintains the blood-brain barrier [1]
In individuals with Alzheimer or Parkinson diseases a marked loss of locus ceruleus neurons was seen, with numerous collections of macrophage-bound and free neuromelanin pigment either with or without AMG (Fig 1C)
The locus ceruleus is close to the fourth ventricle and so could be exposed to toxins in the cerebrospinal fluid [2], but we found that locus ceruleus neurons close to the fourth ventricle did contain more inorganic mercury than those at a greater distance from the ventricle

Summary

Introduction

The locus ceruleus supplies noradrenaline to the central nervous system, by which it influences neuronal and glial function and maintains the blood-brain barrier [1]. Damage to the locus ceruleus with loss of its neurons has been implicated in autopsy studies of conditions as diverse as aging [6], Alzheimer disease [2], Parkinson disease [1], depression [7], bipolar disorder [8], schizophrenia [9] and the sudden infant death syndrome [10]. Recent structural and functional imaging studies have confirmed a loss of locus ceruleus neurons during life in aging and Alzheimer and Parkinson diseases, and have shed light on how decreased noradrenaline leads to changes in locus ceruleus connections that can explain cognitive changes in these conditions [11,12]. Mercury is an attractive candidate for these disorders since humans worldwide are exposed to mercury, via fish consumption and mercury-containing dental restorations [18,19], and mercury has actions that are injurious to cells, the immune system and genes [19]

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