Multimodal Chemical Imaging of Amyloid Plaque Polymorphism

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Multimodal Chemical Imaging of Amyloid Plaque Polymorphism Reveals A# Aggregation Dependent Anionic Lipid Accumulations and Metabolism Wojciech Michno, Ibrahim Kaya, Sofie Nyström, Laurent Guerard, K. Peter R. Nilsson, Per Hammarström, Kaj Blennow, Henrik Zetterberg, and Jörg Hanrieder Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b01361 • Publication Date (Web): 01 Jun 2018 Downloaded from http://pubs.acs.org on June 1, 2018

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Analytical Chemistry

Multimodal Chemical Imaging of Amyloid Plaque Polymorphism Reveals Aβ Aggregation Dependent Anionic Lipid Accumulations and Metabolism Wojciech Michno1, Ibrahim Kaya1, Sofie Nyström2, Laurent Guerard1,3, K. Peter R. Nilsson2, Per Hammarström2, Kaj Blennow1,4, Henrik Zetterberg1,4,5 and Jörg Hanrieder1,5,6*

1) Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden 2) IFM-Department of Chemistry, Linköping University, Linköping, Sweden 3) IMCF Biozentrum, University of Basel, Basel, Switzerland 4) Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden 5) Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom 6) Department of Chemistry and Chemical Engineering, Chalmers University of Technology, Gothenburg, Sweden

* Contact: Jörg Hanrieder, PhD Dept. Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Mölndal Hospital, House V3, SE-43180 Mölndal, Sweden [email protected]; Tel: +46-31-34323771

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Abstract Amyloid plaque formation constitutes one of the main pathological hallmark 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, Aβ 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 Aβ into neurotoxic aggregates and the predominantly cored deposits observed in AD. The structural diversity among Aβ plaques, including cored/compact- and diffuse, may be linked to their distinct Aβ 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 (tgAPPSwe) and was correlated to Aβ 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 localise to the diffuse Aβ structures and correlate with Aβ1-42. Further, lysophospholipids implicated in neuroinflammation were increased in all Aβ 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.

Keywords: Matrix assisted laser/desorption ionization imaging mass spectrometry (MALDI IMS), Alzheimer’s

disease

(AD),

beta-amyloid

(Aβ),

plaque

pathology,

luminescent

oligothiophene (LCOoligothiophenes (LCOs), hyperspectral microscopy, lipids

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conjugated

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Analytical Chemistry

INTRODUCTION Alzheimer's disease (AD) pathology is characterized by morphologically heterogeneous extracellular aggregates consisting of amyloid-β (Aβ) peptides together with intracellular neurofibrillary tangles formed by hyper-phosphorylated tau protein 1. Several lines of evidence suggest that Aβ aggregation is the key pathogenic event in AD and Aβ plaque pathology has hence been a central focus in AD research 2. Aβ plaque polymorphism that precipitates mainly as mature-cored and diffuse aggregates, has been linked to Aβ peptide isoform composition as well as Aβ orientation during formation of crossβ-sheet fibrils 3. Most interestingly, patients with high amyloid load that remain cognitively normal, display only diffuse deposits suggesting formation of mature-cored plaques to be critical for AD pathogenesis 4. Here, soluble, prefibrillar oligomers with distinct β-sheet structures that act as intermediates of mature fibrils have been suggested to play the key role in synaptic dysfunction and neurodegeneration 3,5. However, little is known about the mechanism responsible for the conversion of the monomeric Aβ into neurotoxic aggregates. In addition, plaque associated lipids have been implicated in Aβ plaque polymorphism pathology

6-9

. Indeed, brain lipids have long been implicated in AD

10

. Most prominently, as the ε4 allele encoding the lipid transporter apolipoprotein E4

(APOE4) is the major genetic risk factor for sporadic AD

11

, which strongly suggest that aberrant lipid

homeostasis is tightly linked to Aβ pathogenesis in AD. Imaging mass spectrometry (IMS) is a powerful approach for delineating spatial lipid alterations in situ 12,13

. Here, matrix assisted laser desorption/ionization (MALDI) -based IMS was demonstrated for

probing neuronal lipid chemistry in tissue

12

, particularly with respect to AD pathology, where MALDI-

IMS delineated plaque specific sphingolipid pattern

7,14,15

, and Aβ peptide truncation patterns

16

in

transgenic AD mouse models. Here, transgenics carrying the Swedish mutation (K670N, M671L) of human APP under the Thyr1 promoter (tgAPPSwe) are a good model for probing plaque polymorphism as these mice display both cored and diffuse plaques

17

. Differences in Aβ fibril conformations can be

elucidated using luminescent conjugated oligothiophenes (LCOs)

18

. These fluorescent amyloid

probes, have been shown and verified through antibody staining to differentially recognize mature

3

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fibrillary assemblies as in the cored structure of plaques, as well as immature, protofibrillar Aβ aggregates in diffuse plaques and diffuse halo areas surrounding plaques cored/mature plaques.

19,20

Moreover, these probes vary in their spectroscopic, electro-optic properties, allowing for hyperspectral fluorescent microscopy analysis for annotation of structural heterogenic Aβ pathology

19-21

. These

properties have recently been used to show that Aβ plaque polymorphisms results in characteristic conformational variants within different AD subtypes 21. Herein, we report a novel multimodal imaging paradigm based on histology-compatible MALDI imaging of neuronal lipids

15

along with fluorescent amyloid microscopy using differential LCO staining

and hyperspectral detection. The methodology facilitated the investigation of spatially confined lipid changes associated with Aβ polymorphism in 18 months old tgAPPSwe mice.

EXPERIMENTAL SECTION Chemicals and Reagents All chemicals for matrix and solvent preparation were pro-analysis grade and obtained from SigmaAldrich/Merck (St. Louis, MO), unless otherwise specified. TissueTek optimal cutting temperature (OCT) compound was purchased from Sakura Finetek (AJ Alphen aan den Rijn, The Netherlands).

Tissue Preparation 18 months old tgAPPSwe mice (n=3, 3 male), were investigated (DNr #C17⁄ 14 at Uppsala University) 22

. The brains were dissected (