title: MALDI imaging delineates hippocampal glycosphingolipid changes associated with neurotoxin induced proteopathy following neonatal BMAA exposure.
abstract: The environmental toxin β-N-methylamino-L-alanine (BMAA) has been proposed to contribute to neurodegenerative diseases. We have previously shown that neonatal exposure to BMAA results in dose-dependent cognitive impairments, proteomic alterations and progressive neurodegeneration in the hippocampus of adult rats. A high BMAA dose (460mg/kg) also induced intracellular fibril formation, increased protein ubiquitination and enrichment of proteins important for lipid transport and metabolism. The aim of this study was therefore to elucidate the role of neuronal lipids in BMAA-induced neurodegeneration. By using matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS), we characterized the spatial lipid profile in the hippocampus of six month-old rats that were treated neonatally (postnatal days 9-10) with 460mg/kg BMAA. Multivariate statistical analysis revealed long-term changes in distinct ganglioside species (GM, GD, GT) in the dentate gyrus. These changes could be a consequence of direct effects on ganglioside biosynthesis through the b-series (GM3-GD3-GD2-GD1b-GT1b) and may be linked to astrogliosis. Complementary immunohistochemistry experiments towards GFAP and S100β further verified the role of increased astrocyte activity in BMAA-induced brain damage. This highlights the potential of imaging MS for probing chemical changes associated with neuropathological mechanisms in situ. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.
authors.affiliation: Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institute, 171 76 Stockholm, Sweden; Department of Pharmaceutical Biosciences, Toxicology and Drug Safety, Uppsala University, Box 591, 751 24 Uppsala, Sweden; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Oskar
authors.initials: O
authors.lastname: Karlsson
authors.affiliation: Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal Hospital, House V, 431 80 Mölndal, Sweden.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Michno
authors.affiliation: Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Ransome
authors.affiliation: Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal Hospital, House V, 431 80 Mölndal, Sweden; Department of Chemistry and Chemical Engineering, Analytical Chemistry, Chalmers University of Technology, Kemivägen 10, 412 96 Gothenburg, Sweden; Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, Queen Square, WC1N 3BG London, UK. Electronic address: jh@gu.se.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hanrieder
mesh_terms: D000599:Amino Acids, Diamino / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000087522:Cyanobacteria Toxins; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005732:Gangliosides / Q000378:metabolism; D005911:Gliosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D006028:Glycosphingolipids / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D008055:Lipids / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity*; D011247:Pregnancy; D040901:Proteomics / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods
chemical_list: D000599:Amino Acids, Diamino; D000087522:Cyanobacteria Toxins; D005732:Gangliosides; D006028:Glycosphingolipids; D008055:Lipids; D009498:Neurotoxins; C001824:beta-N-methylamino-L-alanine
keywords: Beta-N-methylamino-L-alanine (BMAA); Environmental toxin; Gliosis; Glycosphingolipids; Imaging mass spectrometry; Protein pathology