Structural amyloid plaque polymorphism is associated with distinct lipid accumulations revealed by trapped ion mobility mass spectrometry imaging

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 is 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 trapped ion mobility spectrometry time‐of‐flight based mass spectrometry imaging (MALDI TIMS TOF MSI) 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 (PUFA)‐conjugated phosphoserines (PS), and PE were depleted at plaques. Hyperspectral amyloid imaging further delineated the unique distribution of PA and PE species to mature plaque core regions, while PI, LPI, GM2 and GM3 lipids localized to immature Aβ aggregates present within the periphery of 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 the differentiation of both distinct lipid components in a complex micro‐environment as well as their correlation to disease‐relevant amyloid plaque polymorphs. Cover Image for this issue: https://doi.org/10.1111/jnc.15390

Tetramodal Chemical Imaging Delineates the Lipid–Amyloid Peptide Interplay at Single Plaques in Transgenic Alzheimer’s Disease Models

“…Further, the data showed accumulation of Aβ peptides that were colocalized with spatial sulfatide alterations as well as the LCO positive features in fluorescence microscopy (Figure E). This is consistent with previous studies showing the depletion of sulfatides at amyloid plaques both in tgArcSwe and tgSwe AD mouse models. ,,, Sulfatides are enriched in the myelin sheath of neurons and are mainly synthesized by oligodendrocytes. ST play vital roles in the regulation of oligodendrocyte maturation and myelin formation. , Further, sulfatide depletion was found to be associated with abnormal ApoE lipoprotein metabolism in both human AD and AD mouse models. , This is of interest as the human APOE ε4 allele encoding apolipoprotein E4 is a major genetic risk factor for AD.…”

“…Subsequent univariate statistics were performed using GraphPad Prism (v.9, GraphPad, San Diego, California). Lipids and peptides were annotated by accurate mass following previous MS/MS-based identifications reported by our group , and others. , …”

Correlative Chemical Imaging and Spatial Chemometrics Delineate Alzheimer Plaque Heterogeneity at High Spatial Resolution

“…Therefore, multiple loading variables may originate from the same species (isotopologues). We acknowledge that the mass accuracy of the used instrumentation limits the separation of isobars, which is however possible to resolve with recent advances within MALDI ion mobility spectrometry MSI. , …”

Ion Mobility Mass Spectrometry for the Separation and Characterization of Small Molecules

“…In order to better understand the physiological and pathological processes, it is vital to capture and present this spatiotemporal change. Matrix-assisted laser desorption ionization (MALDI), − infrared matrix-assisted laser desorption electrospray ionization, , DESI, − nano-DESI, ,, LESA, , LAESI, and other ionization techniques equipped with imaging platform and software can achieve this goal, which is helpful to determine the spatiotemporal correlation between metabolites. Like ambient ionization MS, it faces the challenges of dynamic range, peak capacity, and the ability to identify observed species structurally due to the lack of separation process .…”

“…227 Understanding the mechanism of the disease requires not only exploring the key pathological factors but also observing the surrounding microenvironment. Michno et al 205 used MALDI-TIMS-TOF-MSI combined with hyperspectral confocal microscopy to detect the lipid microenvironment associated with structural polymorphism of amyloid beta plaques in transgenic Alzheimer's disease mice. MALDI-timsTOF-MS can also be used to observe metabolites produced during cell coculture, which is helpful to detect and locate microbial interactions.…”