Plenary Lecture
Speciation of Transition Metals (Manganese and Iron) and Selenium in Brain and at Neural Barriers – The Power of Speciation Methods in Neurodegeneration Research
Professor Bernhard Michalke
Helmholtz-Center Munich - German Research Center for Environmental Health GmbH
Research Unit Analytical BioGeoChemistry
Neuherberg, Germany
E-mail: bernhard.michalke@helmholtz-muenchen.de
Abstract: Transition metals play a crucial role in proper brain function. Misbalances of various metal ions, occasionally induced by overexposure, are known to severely affect brain, resulting in neurodegeneration. As an example, chronic Manganese exposure leads to degeneration of dopaminergic neurons inducing a Parkinson-like complaint called Manganism. Deciphering uncontrolled transport across neural barriers (NB) and the ongoing neurodegenerative mechanisms in the affected brains is still a major task for understanding the complex modes of action.
First we analyzed and identified relevant Mn-carriers (Mn species) being responsible for a widely uncontrolled transport across neural barriers (NB): Mn speciation in paired serum/cerebrospinal fluid (CSF) samples was performed two-dimensionally by SEC-ICP-DRC-MS and CZE-ICP-DRC-MS. The most important Mn-carrier, Mn-citrate, was identified by ESI-FT-ICR-MS. Elevated Mn-citrate concentration in serum were shown to act as marker for increased Mn concentration in CSF (and brain), the latter elevating the risk of Mn-dependent neurological disorders.This change from Mn-transferrin to Mn-citrate was not caused by an overflow of binding sites at transferrin, as also proven by Fe-speciation
Second, to clarify molecular mechanisms of Mn-neurotoxicity we applied SEC-ICP-DRC-MS for Mn-speciation and ESI-FT-ICR-MS and IC-ICP-OES to rat brain extracts after low-dose Mn-feeding, simulating chronic Mn-exposure. ESI-FT-ICR-MS-analysis of brain extracts revealed an increase in oxidative stress markers like glutathione-disulfide (GSSG), prostaglandins, and 15(S)-HETE, a marker for lipid peroxidation. Acetylcholinesterase activity and glutamate concentrations were also increased in brain samples of Mn-supplemented rats, indicating oxidative stress in brain, too. Furthermore, a shift in neuronal Fe(III) to Fe(II) was observed, promoting Fenton reaction and formation of chemical radicals. For the first time altered Fe-species distribution could be related to Mn-induced neuroinflammation, enlarging knowledge of this complex neurodegenerative condition. Additionally, up to several hundred metabolites were shifted under Mn exposure but not uniformly. Metabolites correlated either positively to specific Mn-species, and others negatively. The combination of various speciation- and different mass spectrometry techniques provided information how Mn enters the brain without efficient control at NB and provided substantial evidence that Mn-induced neuroinflammation leads to oxidative stress triggered by multifactorial pathophysiological processes. As an additional example, Se-speciation in paired serum/CSF samples from amyotrophic lateral sclerosis (ALS) patients shows correlations between distinct Se-species (in contrast to total Se) and ALS prevalence.
Brief Biography of the Speaker: Prof. Dr. Bernhard Michalke is leader of the research group "Elements and Element Speciation" and of the "Central Inorganic Analysis Division" since 2005 as well as deputy director of the research unit "Analytical BioGeoChemistry" at the Helmholtz Center Munich - German Research Center for Environmental Health since 2009. He received his Diploma and his PhD (Dr. rer. nat.) in 1985 and 1988 from the Technical University of Munich. Since 1988, he is principal researcher at the Helmholtz Center Munich. His research interests encompass speciation projects related to environmental health, i.e. the exposure and chemical speciation of neuro-degenerative elements such as manganese and species related neuro-toxic effects in the central nervous system. Since 1996 he is also lecturer at the Institute of Analytical Chemistry and Food Chemistry of the Technical University of Graz, Austria, where he received his habilitation (Dr. habil.) in analytical chemistry in 1999. Prof. Dr. Bernhard Michalke has published more than 175 peer reviewed articles and 10 book chapters. His first edited book “Metallomics - Analytical techniques and Speciation Methods” was published in 2016. Since 1998, he has been co-organizer of several international conferences.