The toxic metal hypothesis for neurological disorders

Abstract

Multiple sclerosis and the major sporadic neurogenerative disorders, amyotrophic lateral sclerosis, Parkinson disease, and Alzheimer disease are considered to have both genetic and environmental components. Advances have been made in finding genetic predispositions to these disorders, but it has been difficult to pin down environmental agents that trigger them. Environmental toxic metals have been implicated in neurological disorders, since human exposure to toxic metals is common from anthropogenic and natural sources, and toxic metals have damaging properties that are suspected to underlie many of these disorders. Questions remain, however, as to how toxic metals enter the nervous system, if one or combinations of metals are sufficient to precipitate disease, and how toxic metal exposure results in different patterns of neuronal and white matter loss. The hypothesis presented here is that damage to selective locus ceruleus neurons from toxic metals causes dysfunction of the blood-brain barrier. This allows circulating toxicants to enter astrocytes, from where they are transferred to, and damage, oligodendrocytes, and neurons. The type of neurological disorder that arises depends on (i) which locus ceruleus neurons are damaged, (ii) genetic variants that give rise to susceptibility to toxic metal uptake, cytotoxicity, or clearance, (iii) the age, frequency, and duration of toxicant exposure, and (iv) the uptake of various mixtures of toxic metals. Evidence supporting this hypothesis is presented, concentrating on studies that have examined the distribution of toxic metals in the human nervous system. Clinicopathological features shared between neurological disorders are listed that can be linked to toxic metals. Details are provided on how the hypothesis applies to multiple sclerosis and the major neurodegenerative disorders. Further avenues to explore the toxic metal hypothesis for neurological disorders are suggested. In conclusion, environmental toxic metals may play a part in several common neurological disorders. While further evidence to support this hypothesis is needed, to protect the nervous system it would be prudent to take steps to reduce environmental toxic metal pollution from industrial, mining, and manufacturing sources, and from the burning of fossil fuels.

Keywords: Alzheimer disease; Parkinson disease; amyotrophic lateral sclerosis; astrocytes; locus ceruleus; multiple sclerosis; oligodendrocytes; toxic metals.

Figure 1

The toxic metal hypothesis for neurological disorders. Human exposure to multiple toxic metals results in selective uptake of the metals into locus ceruleus neurons. Decreased noradrenaline from the locus ceruleus causes multifocal damage to the blood–brain barrier, allowing toxic metal uptake by astrocytes. A second pathway is slower age-related accumulation of toxic metals through an intact blood–brain barrier. Toxic metals in astrocytes cause astrocyte dysfunction, and transfer of metals from astrocytes triggers neuronal and oligodendrocyte malfunction. The degree of toxic metal-induced damage to these cells differs due to genetic variants and different combinations of toxic metals, leading to varying clinical outcomes. Uptake of toxic metals by extra-CNS organs is responsible for systemic disorders associated with neurological disorders. Uptake of toxic metals by striated muscles is followed by retrograde transport of metals to the lower motor neurons affected by ALS.

Figure 2

Mercury in the brain after exposure to inorganic mercury. (A) Dense black AMG™ staining is seen in two locus ceruleus neurons (closed arrowheads) and scattered in the neuromelanin pigment in another two neurons (open arrowheads). (B) In the frontal cortex, AMG™ (combined with brown GFAP immunostaining) are present in the frontal lobe brown glia limitans (arrow) below the cerebrospinal fluid (CSF), in brown subpial astrocyte cell bodies (closed arrowhead), in brown astrocyte processes (open arrowhead), and in blood vessel walls. (C) In the frontal cortex, AMG™ (closed arrowhead) are seen in an oligodendrocyte cell body adjacent to the nucleus (thin arrow). The GFAP-stained brown descending branch of an interlaminar astrocyte makes contact (open arrowhead) with the oligodendrocyte. (D) In the frontal cortex, AMG™ are seen in the cell body of a corticomotoneuron (closed arrowhead), a dendrite (small arrow), a GFAP-stained brown connecting astrocyte process (large arrow), and largely obscuring the brown astrocyte cell body (open arrowhead). (E) In the frontal white matter, GFAP-stained brown fibrous astrocyte cell bodies (open arrowheads) and processes (closed arrowheads) contain AMG™. No AMG™ are seen in oligodendrocytes (in circles). (F) In the pineal gland, AMG™ are present in most pinealocytes (closed arrowheads) and in blood vessel walls. BV blood vessel. Methods: A–E adapted from (23), F from (25). Bars = 20 μm.

Figure 3

Mercury in brain and other organs after intermittent exposure to organic mercury. (A) In the locus ceruleus, dense black AMG™ staining is seen in most neurons (closed arrowheads). (B) AMG™ are present in cerebellar dentate neurons (closed arrowheads). (C) In the lateral geniculate nucleus, AMG™ staining is seen in a GFAP-immunostained brown perivascular astrocyte (open arrowhead), in nearby neurons (closed arrowheads), and in an oligodendrocyte (small arrow). (D) Many chromaffin cells in the adrenal medulla contain AMG™. (E) Most thyroid follicular cells contain AMG™. (F) Renal proximal tubule cells contain AMG™ (closed arrowhead), but not distal tubules (open arrowhead) or glomeruli (arrow). BV blood vessel. Methods: A (22), B (26), C adapted from (25), D (34), E (35), F (36). Bars = 20 μm.

Figure 4

Silver in the brain from a man with an unknown source of exposure. (A) In the locus ceruleus, dense black AMG™ staining is seen in two neurons (closed arrowheads). Another two neurons are AMG™-free (open arrowheads). (B) In the anterior pontine white matter, AMG™ staining is present in the walls of a branching microvessel. In the magnified box (at right) paranuclear AMG™ deposits (thin arrow) are seen in oligodendrocytes. (C) AMG™ are prominent in microvessels (closed arrowhead) and in glial cells (small arrow) in the inferior olive white matter in the medulla oblongata. No AMG™ are present in blood vessels, glial cells, or neurons (open arrowheads) in the grey matter of the adjacent inferior olivary nucleus. (D) In the inferior olive white matter in the medulla oblongata, AMG™ are present in the cytoplasm of astrocytes (open arrowheads) and oligodendrocytes (thin arrows). (E) AMG™ are present in endothelial cells (closed arrowhead) of a venule deep in the lateral occipitotemporal gyrus of the inferomedial temporal lobe, and in small superficial cortical cells adjacent to the venule (open arrowhead). Inset is a magnification of the dashed rectangle. (F) A venule (bottom right) in the anterior pons has AMG™ in its endothelial cells (closed arrowhead). Adjacent pontine neurons (open arrowheads) contain AMG™. Methods: A,E,F (26), B–D adapted from (26). Bars = 20 μm.

Figure 5

Toxic metals in MS brains. (A) In the locus ceruleus, black AMG™ grains are seen in most neurons (closed arrowheads). Some neurons contain no AMG™ (open arrowheads). (B) In the pontine white matter, small AMG™ deposits are seen in the wall of a blood vessel (open arrow) and in surrounding macrophages (thin arrows) in the perivascular space (PVS). GFAP-immunostained brown fibrous astrocytes (open arrowheads) near the blood vessel contain AMG™. Inset: magnified view of an astrocyte containing AMG™ (closed arrowhead). (C) In the cerebral cortex, a small leptomeningeal blood vessel (BV) contains AMG™ in its wall (left magnified inset, closed arrowhead). Right magnified inset: a microvessel within the cortex contains AMG™ (arrow), with an adjacent GFAP-stained brown astrocyte cell body connected via a hypertrophic process (open arrowhead). Middle inset: a white matter (WM) AMG™-containing microvessel (arrow) connects to an astrocyte cell body via a hypertrophic astrocytic process (open arrowhead). (D) In the cerebral white matter, oligodendrocytes (arrow) and GFAP-stained brown astrocytes (open arrowhead) adjacent to a blood vessel contain AMG™ (magnified in inset). (E) Pontine white matter microvessels (closed arrowhead) contain more AMG™ than grey matter microvessels (open arrowhead). (F) In the frontal white matter, AMG™ are seen in a microvessel wall (open arrowhead) and in surrounding pericytes (closed arrowheads in magnified upper inset). Lower magnified inset: scattered oligodendrocytes have small AMG™ deposits (arrow). BV blood vessel. Methods: A–F adapted from (26). Bars = 20 μm.

Figure 6

Toxic metals in the pons of a person with MS. Posterior pons: metals present in the locus ceruleus (within dashed circles) are silver, aluminium, iron, mercury, nickel, and lead. Iron and nickel are seen in subpial regions adjacent to the cerebrospinal fluid (arrowheads). Anterior pons: silver, iron and lead are present in white matter regions, and iron around blood vessels (arrow). Methods: adapted from (26).

Figure 7

The toxic metal hypothesis in MS. (A) Circulating toxic metals enter the perivascular space. (1) Toxic metals in locus ceruleus neurons cause a localized noradrenaline deficiency in a postcapillary venule, which impairs the blood–brain barrier. (2) Circulating toxic metals activate lymphocytes and monocytes. (3) Toxic metals in endothelial cells and pericytes further damage the blood–brain barrier. (4) Toxic metals enter the perivascular space from the circulation (first entry). (5) Toxic metals exiting the brain via cerebrospinal fluid and astrocytes enter the perivascular space (second entry). (6) Toxic metals activate perivascular space macrophages. (B) Toxic metals enter astrocytes and oligodendrocytes. (1) Toxic metals enter astrocytes from the perivascular space. (2) Astrocytes transfer toxic metals into oligodendrocytes through gap junctions. (3) Toxic metals activate astrocyte toxicity toward oligodendrocytes. (4) Oligodendrocytes undergo apoptosis. (5) Demyelination of axons. (C) Secondary autoimmune inflammation. (1) Activated circulating white blood cells enter the perivascular space. (2) White blood cells pass into the brain parenchyma. (3) Myelin debris and toxic metals incite an autoimmune inflammatory response. ABM astrocyte basement membrane, EBM endothelial basement membrane, END endothelial cells. Diagram adapted from Mastorakos and McGavern 2019 (157). Reprinted with permission from AAAS.

Figure 8

Potential roles played by toxic metals (TMs) in MS. Genetic variants, low sun exposure and/or vitamin D, or Epstein–Barr virus (EBV) infection increase susceptibility to metal toxicity or autoimmunity. White matter demyelination: The blood–brain barrier is focally disrupted by a lack of noradrenaline from toxic metal-containing locus ceruleus neurons. This allows toxic metals to enter perivascular spaces in the white matter, followed by uptake into astrocytes and oligodendrocytes, oligodendrocyte apoptosis, and secondary autoimmune inflammation. Interactions between multiple toxic metals, and displacement of essential metals, increase toxicity. Clinically isolated syndrome: With no further toxic metal exposure, only one episode of demyelination occurs. Cortical demyelination: A similar pathway originating in the perivascular spaces of the meninges and cortex results in cortical demyelination. Relapsing–remitting MS: Repeated exposures to toxic metals lead to further episodes of demyelination. Progressive MS: Progressive disease is caused by combinations of (i) toxic metal accumulation in neurons causing neurodegeneration, (ii) toxic metals at plaque margins causing expansion, (iii) increased episodes of cortical demyelination, and (iv) the transformation of organic to more toxic inorganic metals.

Figure 9

Toxic metals in upper and lower motor neurons and in ALS locus ceruleus neurons. (A) Dense AMG™ staining is seen in two corticomotoneurons (closed arrowheads) in the frontal motor cortex from a person with Parkinson disease. Nearby oligodendrocytes contain AMG™ deposits (open arrowhead). (B) AMG™ staining is seen in a spinal motor neuron (closed arrowhead), as well as in a small interneuron (open arrowhead) in a control spinal cord. (C) In the locus ceruleus of a person with ALS, dense AMG™ staining obscures the neuromelanin in one neuron (closed arrowhead). Sparse AMG™ grains are present in the neuromelanin of another neuron (open arrow). Other neuromelanin-containing neurons (open arrowheads), and a neuron without neuromelanin (thin arrow), are AMG™-free. Methods: A adapted from (25), B from (158), C (18). Bars = 20 μm.

Figure 10

Toxic and essential metals in human striated muscle. In this muscle from a person with no neurological disorder, essential elements, such as copper (Cu), phosphorus (P), selenium (Sn) and zinc (Zn) are present in all myofibres. Some toxic metals, such as silver (Ag) and cadmium (Cd) are also seen in most myofibres. The toxic metals lead (Pb), cobalt (Co), chromium (Cr) and tin (Sn) are present in the fibrous connective tissue between muscle fascicles, which is supplied with large blood vessels. Iron (Fe) is present in blood vessels because of the high iron content of red blood cells. Method: LA-ICP-MSI as used in (26).

Figure 11

The toxic metal hypothesis in ALS. Damage to locus ceruleus neurons weakens the blood–brain barrier and increases the susceptibility of motor neurons to toxicant damage. Toxic metals enter corticomotoneurons and nearby oligodendrocytes via astrocytes. Spinal motor neurons undergo hyperexcitability from toxicant-induced damage to corticomotoneurons and inhibitory interneurons and are loaded with toxicants by retrograde axonal uptake from muscles. Normal transmission: + excitatory, − inhibitory. Exercise +: toxic metal uptake increased with exercise. Diagram adapted from (158).

Figure 12

Toxic metals in a patient with concurrent ALS and MS. (A) Most locus ceruleus neurons contain dense black AMG™ (closed arrowheads). Some neurons have no (open arrowhead) or only slight (arrow) AMG™ staining. (B) A corticomotoneuron cell body has AMG™ in both the lipofuscin (closed arrowhead) and in the remaining perikaryon (open arrowhead). (C) One slightly shrunken spinal motor neuron has AMG™ in the perikaryon (closed arrowhead) and in its processes (open arrowheads). An adjacent motor neuron (arrow) contains no AMG™ (arrow). (D) Brain microvessels have AMG™ in their walls (closed arrowhead). Nearby oligodendrocytes or pericytes have small paranuclear AMG™ deposits (open arrowheads). Methods: A–D (18). Bars = 20 μm.

Figure 13

Toxic metals in PD brains and pituitary glands. (A) In locus ceruleus neurons, magenta a-synuclein immunostaining shows co-localization of Lewy bodies (open arrowheads) with black-staining AMG™. No Lewy bodies are present in a neuron not containing AMG™ (closed arrowhead). The inset shows AMG™ within a magenta-stained Lewy body. (B) A locus ceruleus neuron contains a magenta-stained Lewy body (open arrowhead) partially surrounded by dense AMG™ (closed arrows), adjacent to the nucleus (arrow). (C) In the substantia nigra, brown a-synuclein immunostaining shows co-localization of a Lewy body (open arrow) with black AMG™ (closed arrow) in a neuron (nucleus shown by closed arrow). A brown Lewy neurite (upper inset) contains a few black AMG™ grains (open arrow). Scattered oligodendrocytes have small AMG™ deposits (thin arrows). Left inset: AMG™ staining co-localizes with a magenta-stained Lewy body. (D) In the thalamus, AMG™ grains are present in the cytoplasm of most neurons (open arrowheads). Magnified view of one neuron shown in upper inset. Numerous oligodendrocytes have small AMG™ deposits (arrows). AMG™ staining co-localizes with a brown Lewy body in one neuron (lower inset). (E) In the putamen, AMG™ grains (open arrowheads) are present in medium-sized neurons (one enlarged in the upper inset). Large neurons (open arrows) contain no AMG™. Small AMG™ deposits are present in scattered oligodendrocytes (arrow) and pericytes (closed arrowhead). (F) In the anterior pituitary, AMG™ grains are present in scattered, red-immunostained growth hormone-containing cells (arrowheads). Methods: A–E adapted from (25), F (55). Bars = 20 μm.

Figure 14

Toxic metals in PD brains detected on LA-ICP-MSI. (A–C) Posterior pons. Mercury (A), iron (B), and aluminium (C) are prominent in the locus ceruleus (dashed outlines). (D–F) Hippocampus. A high nuclear density, shown by the phosphorus image (D), is present in the hippocampal white matter (top, dashed outline) as well as in the dentate gyrus (arrow). A large amount of iron (E) is present in the hippocampal white matter (top, dashed outline), and in grey matter adjacent to the dentate gyrus (asterisk). Particulate mercury (F) is seen in the hippocampal white matter (arrow) in the dashed outline. (G–I) Frontal white matter. The high nuclear density of the frontal white matter (dashed outline) is shown in the phosphorus image (G). The the frontal white matter, shown by the phosphorus image (G), contains more iron (H) than the frontal cortex, where most iron is in the deeper cortical layers (*) adjacent to the white matter. Particulate mercury (I) is present in the frontal white matter. Scale = counts per second (proportional to abundance). Fig adapted from (25).