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Structural Amyloid Plaque Polymorphism is Associated with Distinct Lipid Accumulations Revealed by Trapped Ion Mobility Mass Spectrometry Imaging (TIMS MSI)

Michno, W; Wehrli, PM; Koutarapu, S; Marsching, C; Minta, K; Ge, J; Meyer, SW; ... Hanrieder, J; + view all (2021) Structural Amyloid Plaque Polymorphism is Associated with Distinct Lipid Accumulations Revealed by Trapped Ion Mobility Mass Spectrometry Imaging (TIMS MSI). Journal of Neurochemistry 10.1111/jnc.15557. (In press). Green open access

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Abstract

Understanding of Alzheimer’s disease (AD) pathophysiology, requires molecular assessment of how key pathological factors, specifically amyloid β (Aβ) plaques, influence the surrounding microenvironment. Here, neuronal lipids have been implicated in Aβ) plaque pathology, though the lipid microenvironment in direct proximity to Aβ plaques are still not fully resolved. A further challenge is the microenvironmental molecular heterogeneity, across structurally polymorphic Aβ features - such as diffuse, immature and mature, fibrillary aggregates, whose resolution requires the integration of advanced, multimodal chemical imaging tools. Herein, we used matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) trapped ion mobility spectrometry Time-of-Flight (TIMS TOF) in combination with hyperspectral confocal microscopy to probe the lipidomic microenvironment associated with structural polymorphism of Aβ plaques in transgenic Alzheimer’s disease mice (tgAPPSWE). Using on tissue and ex situ validation, TIMS MS/MS facilitated unambiguous identification of isobaric lipid species that showed plaque pathology associated localizations. Integrated multivariate imaging data analysis revealed multiple, Aβ plaque enriched lipid patterns for gangliosides (GM), phosphoinositols (PI), phosphoethanolamines (PE) and phosphatidic acids (PA). Conversely, sulfatides (ST), cardiolipins (CL) and polyunsaturated fatty acid conjugated -phosphoserines (PS) and - PE were depleted at plaques. Hyperspectral amyloid imaging further delineated unique distribution of PA, PE to mature plaque core regions, while PI, LPI, GM2 and GM3 localized to immature Aβ aggregates present within the periphery of individual Aβ plaques. Finally, we followed AD pathology associated lipid changes over time, identifying plaque growth and maturation to be characterized by peripheral accumulation of PI (18:0/22:6). Together, these data demonstrate the potential of multimodal imaging approaches to overcome limitations associated with conventional advanced MS imaging applications. This allowed for differentiation of both distinct lipid components in a complex micro environment, as well as their correlation to disease relevant amyloid plaque polymorphs.

Type: Article
Title: Structural Amyloid Plaque Polymorphism is Associated with Distinct Lipid Accumulations Revealed by Trapped Ion Mobility Mass Spectrometry Imaging (TIMS MSI)
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/jnc.15557
Publisher version: https://doi.org/10.1111/jnc.15557
Language: English
Additional information: © 2021 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10140382
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