A marked loss of locus ceruleus (LC) neurons is a striking pathological feature of Alzheimer's disease (AD). LC neurons are particularly prone to taking up circulating toxicants such as heavy metals, and hyperphosphorylated tau (tau(HYP)) appears early in these neurons. In an attempt to find out if both heavy metals and tau(HYP) could be damaging LC neurons, we looked in the LC neurons of 21 sporadic AD patients and 43 non-demented controls for the heavy metals mercury, bismuth, and silver using autometallography, and for tau(HYP) using AT8 immunostaining. Heavy metals or tau(HYP) were usually seen in separate LC neurons, and rarely co-existed within the same neuron. The number of heavy metal-containing LC neurons did not correlate with the number containing tau(HYP). Heavy metals therefore appear to occupy a mostly different population of LC neurons to those containing tau(HYP), indicating that the LC in AD is vulnerable to two different assaults. Reduced brain noradrenaline from LC damage is linked to amyloid-β deposition, and tau(HYP) in the LC may seed neurofibrillary tangles in other neurons. A model is described, incorporating the present findings, that proposes that the LC plays a part in both the amyloid-β and tau pathologies of AD.
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.
BackgroundEnvironmental toxins are suspected to play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS). In an attempt to determine which pathways these toxins can use to enter motor neurons we compared the distribution of mercury in the CNS of a human and of mice that had been exposed to inorganic mercury.ResultsIn the human who had been exposed to metallic mercury, mercury was seen predominantly in the locus ceruleus and corticomotor neurons, as well as in scattered glial cells. In mice that had been exposed to mercury vapor or mercuric chloride, mercury was present in lower motor neurons in the spinal cord and brain stem.ConclusionsIn humans, inorganic mercury can be taken up predominantly by corticomotor neurons, possibly when the locus ceruleus is upregulated by stress. This toxin uptake into corticomotor neurons is in accord with the hypothesis that ALS originates in these upper motor neurons. In mice, inorganic mercury is taken up predominantly by lower motor neurons. The routes toxins use to enter motor neurons depends on the nature of the toxin, the duration of exposure, and possibly the amount of stress (for upper motor neuron uptake) and exercise (for lower motor neuron uptake) at the time of toxin exposure.
Neurotoxic metals have been implicated in the pathogenesis of multiple sclerosis, neurodegenerative disorders and brain tumours but studies of the location of heavy metals in human brains are rare. In a man who injected himself with metallic mercury the cellular location of mercury in his brain was studied after 5 months of continuous exposure to inorganic mercury arising from metallic mercury deposits in his organs. Paraffin sections from the primary motor and sensory cortices and the locus ceruleus in the pons were stained with autometallography to detect inorganic mercury and combined with glial fibrillary acidic protein immunohistochemistry to identify astrocytes. Inorganic mercury was found in grey matter subpial, interlaminar, protoplasmic and varicose astrocytes, white matter fibrous astrocytes, grey but not white matter oligodendrocytes, corticomotoneurons and some locus ceruleus neurons. In summary, inorganic mercury is taken up by five types of human brain astrocytes, as well as by cortical oligodendrocytes, corticomotoneurons and locus ceruleus neurons. Mercury can induce oxidative stress, stimulate autoimmunity and damage DNA, mitochondria and lipid membranes, so its location in these CNS cells suggests it could play a role in the pathogenesis of multiple sclerosis, neurodegenerative conditions such as Alzheimer’s disease and amyotrophic lateral sclerosis, and glial tumours.
BackgroundThe causes of sporadic amyotrophic lateral sclerosis (SALS) and other types of motor neuron disease (MND) remain largely unknown. Heavy metals have long been implicated in MND, and it has recently been shown that inorganic mercury selectively enters human locus ceruleus (LC) and motor neurons. We therefore used silver nitrate autometallography (AMG) to look for AMG-stainable heavy metals (inorganic mercury and bismuth) in LC and motor neurons of 24 patients with MND (18 with SALS and 6 with familial MND) and in the LC of 24 controls.ResultsHeavy metals in neurons were found in significantly more MND patients than in controls when comparing: (1) the presence of any versus no heavy metal-containing LC neurons (MND 88%, controls 42%), (2) the median percentage of heavy metal-containing LC neurons (MND 9.5%, control 0.0%), and (3) numbers of individuals with heavy metal-containing LC neurons in the upper half of the percentage range (MND 75%, controls 25%). In MND patients, 67% of remaining spinal motor neurons contained heavy metals; smaller percentages were found in hypoglossal, nucleus ambiguus and oculomotor neurons, but none in cortical motor neurons. The majority of MND patients had heavy metals in both LC and spinal motor neurons. No glia or other neurons, including neuromelanin-containing neurons of the substantia nigra, contained stainable heavy metals.ConclusionsUptake of heavy metals by LC and lower motor neurons appears to be fairly common in humans, though heavy metal staining in the LC, most likely due to inorganic mercury, was seen significantly more often in MND patients than in controls. The LC innervates many cell types that are affected in MND, and it is possible that MND is triggered by toxicant-induced interactions between LC and motor neurons.
Amyotrophic lateral sclerosis (ALS) is a devastating late-onset neurodegenerative disorder in which only a small proportion of patients carry an identifiable causative genetic lesion. Despite high heritability estimates, a genetic etiology for most sporadic ALS remains elusive. Here we report the epigenetic profiling of five monozygotic twin pairs discordant for ALS, four with classic ALS and one with the progressive muscular atrophy ALS variant, in whom previous whole genome sequencing failed to uncover a genetic basis for their disease discordance. By studying cytosine methylation patterns in peripheral blood DNA we identified thousands of large between-twin differences at individual CpGs. While the specific sites of differences were mostly idiosyncratic to a twin pair, a proportion involving GABA signalling were common to all ALS individuals. For both idiosyncratic and common sites the differences occurred within genes and pathways related to neurobiological functions or dysfunctions, some of particular relevance to ALS such as glutamate metabolism and the Golgi apparatus. All four classic ALS patients were epigenetically older than their unaffected co-twins, suggesting accelerated aging in multiple tissues in this disease. In conclusion, widespread changes in methylation patterns were found in ALS-affected co-twins, consistent with an epigenetic contribution to disease. These DNA methylation findings could be used to develop blood-based ALS biomarkers, gain insights into disease pathogenesis, and provide a reference for future large-scale ALS epigenetic studies.
Damage to the retina and optic nerve is found in some neurodegenerative disorders, but it is unclear whether the optic pathway and central nervous system (CNS) are affected by the same injurious agent, or whether optic pathway damage is due to retrograde degeneration following the CNS damage. Finding an environmental agent that could be responsible for the optic pathway damage would support the hypothesis that this environmental toxicant also triggers the CNS lesions. Toxic metals have been implicated in neurodegenerative disorders, and mercury has been found in the retina and optic nerve of experimentally-exposed animals. Therefore, to see if mercury exposure in the prenatal period could be one link between optic pathway damage and human CNS disorders of later life, we examined the retina and optic nerve of neonatal mice that had been exposed prenatally to mercury vapor, using a technique, autometallography, that detects the presence of mercury within cells. Pregnant mice were exposed to a non-toxic dose of mercury vapor for four hours a day for five days in late gestation, when the mouse placenta most closely resembles the human placenta. The neonatal offspring were sacrificed one day after birth and gapless serial sections of formalin-fixed paraffin-embedded blocks containing the eyes were stained with silver nitrate autometallography to detect inorganic mercury. Mercury was seen in the nuclear membranes of retinal ganglion cells and endothelial cells. A smaller amount of mercury was present in the retinal inner plexiform and inner nuclear layers. Mercury was conspicuous in the peripapillary retinal pigment epithelium. In the optic nerve, mercury was seen in the nuclear membranes and processes of glia and in endothelial cells. Optic pathway and CNS endothelial cells contained mercury. In conclusion, mercury is taken up preferentially by fetal retinal ganglion cells, optic nerve glial cells, the retinal pigment epithelium, and endothelial cells. Mercury induces free radical formation, autoimmunity, and genetic and epigenetic changes, so these findings raise the possibility that mercury plays a part in the pathogenesis of degenerative CNS disorders that also affect the retina and optic nerve.
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