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Multimodal Chemical Imaging of Amyloid Plaque Polymorphism Reveals A beta Aggregation Dependent Anionic Lipid Accumulations and Metabolism

Journal article
Authors Wojciech Michno
Ibrahim Kaya
S. Nystrom
Laurent Guerard
K. P. R. Nilsson
P. Hammarstrom
Kaj Blennow
Henrik Zetterberg
Jörg Hanrieder
Published in Analytical Chemistry
Volume 90
Issue 13
Pages 8130-8138
ISSN 0003-2700
Publication year 2018
Published at Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Pages 8130-8138
Language en
Links dx.doi.org/10.1021/acs.analchem.8b0...
Keywords immunoprecipitation-mass-spectrometry, alzheimers-disease, microglial, response, cerebrospinal-fluid, apolipoprotein-e, transgenic mice, diffuse plaques, protein smsr, mouse model, ceramide, Chemistry
Subject categories Neurosciences

Abstract

Amyloid plaque formation constitutes one of the main pathological hallmarks of Alzheimer's disease (AD) and is suggested to be a critical factor driving disease pathogenesis. Interestingly, in patients that display amyloid pathology but remain cognitively normal, A beta deposits are predominantly of diffuse morphology suggesting that cored plaque formation is primarily associated with cognitive deterioration and AD pathogenesis. Little is known about the molecular mechanism responsible for conversion of monomeric A beta into neurotoxic aggregates and the predominantly cored deposits observed in AD. The structural diversity among A beta plaques, including cored/compact- and diffuse, may be linked to their distinct A beta profile and other chemical species including neuronal lipids. We developed a novel, chemical imaging paradigm combining matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) and fluorescent amyloid staining. This multimodal imaging approach was used to probe the lipid chemistry associated with structural plaque heterogeneity in transgenic AD mice (tgAPP(Swe)) and was correlated to A beta profiles determined by subsequent laser microdissection and immunoprecipitation-mass spectrometry. Multivariate image analysis revealed an inverse localization of ceramides and their matching metabolites to diffuse and cored structures within single plaques, respectively. Moreover, phosphatidylinositols implicated in AD pathogenesis, were found to localize to the diffuse A beta structures and correlate with A beta 1-42. Further, lysophospholipids implicated in neuroinflammation were increased in all A beta deposits. The results support previous clinical findings on the importance of lipid disturbances in AD pathophysiology and associated sphingolipid processing. These data highlight the potential of multimodal imaging as a powerful technology to probe neuropathological mechanisms.

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