Manganese Caused Neurodegeneration in Non-Human Primates

Tomas R. Guilarte, Ph.D.
Department of Environmental Health Sciences, Johns Hopkins University
NIEHS Grants R01ES010975

Although manganese is an essential trace element in the diets of mammals, high concentrations in the brain produce neurological disease. The source of these toxic levels can be from naturally occurring or man-made sources in the environment and also from occupational exposures. Additionally, injectible psychostimulant drugs can contain enough manganese to produce parkinsonian-like symptoms. There is current concern that exposure to manganese from a gasoline additive may increase the body burden of manganese and lead to higher incidence of neurological disease.

An NIEHS grantee at Johns Hopkins University investigated gene expression changes in response to manganese exposures in cynomologus macaques, also known as crab-eating macaques or long-tailed macaques. Previous research has shown that these monkeys have slight cognitive and fine motor deficits in response to manganese exposure. The results show that 61 genes were up-regulated and four genes had lower activity relative to the controls out of a total of 6,766 genes examined. The affected genes were associated with a variety of cellular activities including DNA repair, apoptosis, protein folding, inflammation, etc. The gene coding for a member of the amyloid precursor protein family, amyloid-beta precursor-like protein 1, was the most highly up-regulated gene. Amyloid proteins are responsible for the protein plaques seen in Alzheimer's patients. These changes were seen in the frontal cortex, a region of the brain not previously associated with manganese neurotoxicity.

These results provide new evidence on manganese-induced effects in the frontal cortex which accumulates much lower concentrations of manganese than other brain regions. These data suggest that manganese-induced neurodegeneration cannot be solely defined by the concentration of manganese in brain tissue, but also by the sensitivity of particular brain regions.

Citation: Guilarte TR, Burton NC, Verina T, Prabhu VV, Becker KG, Syversen T, Schneider JS. Increased APLP1 expression and neurodegeneration in the frontal cortex of manganese-exposed non-human primates. J Neurochem. 2008 Mar 17; Epub ahead of print.