title: Delineating Amyloid Plaque Associated Neuronal Sphingolipids in Transgenic Alzheimer's Disease Mice (tgArcSwe) Using MALDI Imaging Mass Spectrometry.
abstract: The major pathological hallmarks of Alzheimer's disease (AD) are the progressive aggregation and accumulation of beta-amyloid (Aβ) and hyperphosphorylated tau protein into neurotoxic deposits. Aβ aggregation has been suggested as the critical early inducer, driving the disease progression. However, the factors that promote neurotoxic Aβ aggregation remain elusive. Imaging mass spectrometry (IMS) is a powerful technique to comprehensively elucidate the spatial distribution patterns of lipids, peptides, and proteins in biological tissue sections. In the present study, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS)-based imaging was used on transgenic Alzheimer's disease mouse (tgArcSwe) brain tissue to investigate the sphingolipid microenvironment of individual Aβ plaques and elucidate plaque-associated sphingolipid alterations. Multivariate data analysis was used to interrogate the IMS data for identifying pathologically relevant, anatomical features based on their lipid chemical profile. This approach revealed sphingolipid species that distinctly located to cortical and hippocampal deposits, whose Aβ identity was further verified using fluorescent amyloid staining and immunohistochemistry. Subsequent multivariate statistical analysis of the spectral data revealed significant localization of gangliosides and ceramides species to Aβ positive plaques, which was accompanied by distinct local reduction of sulfatides. These plaque-associated changes in sphingolipid levels implicate a functional role of sphingolipid metabolism in Aβ plaque pathology and AD pathogenesis. Taken together, the presented data highlight the potential of imaging mass spectrometry as a powerful approach for probing Aβ plaque-associated lipid changes underlying AD pathology.
authors.affiliation: Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg , 431 80 Mölndal, Sweden.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Kaya
authors.affiliation: Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg , 431 80 Mölndal, Sweden.|Department of Chemistry and Molecular Biology, University of Gothenburg , 412 96 Gothenburg, Sweden.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Brinet
authors.affiliation: Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg , 431 80 Mölndal, Sweden.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Michno
authors.affiliation: Department of Public Health and Caring Sciences, Uppsala University , 752 37 Uppsala, Sweden.
authors.forename: Stina
authors.initials: S
authors.lastname: Syvänen
authors.affiliation: Department of Public Health and Caring Sciences, Uppsala University , 752 37 Uppsala, Sweden.
authors.forename: Dag
authors.initials: D
authors.lastname: Sehlin
authors.affiliation: Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg , 431 80 Mölndal, Sweden.|Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , 431 80 Mölndal, Sweden.|Department of Molecular Neuroscience, UCL Institute of Neurology, University College London , London WC1N 3BG, United Kingdom.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg , 431 80 Mölndal, Sweden.|Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , 431 80 Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg , 431 80 Mölndal, Sweden.|Department of Molecular Neuroscience, UCL Institute of Neurology, University College London , London WC1N 3BG, United Kingdom.|Department of Chemistry and Chemical Engineering, Chalmers University of Technology , 412 96 Gothenburg, Sweden.
authors.forename: Jörg
authors.identifier: 0000-0001-6059-198X
authors.initials: J
authors.lastname: Hanrieder
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics; D058225:Plaque, Amyloid / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013107:Sphingolipids / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D013107:Sphingolipids
keywords: Alzheimer’s disease; MALDI imaging mass spectrometry; amyloid-β plaque pathology; sphingolipids; tgArcSwe