Computational Analysis of Alzheimer Amyloid Plaque Composition in 2D- and Elastically Reconstructed 3D-MALDI MS Images

Abstract

MALDI mass spectrometry imaging (MSI) enables label-free, spatially resolved analysis of a wide range of analytes in tissue sections. Quantitative analysis of MSI datasets is typically performed on single pixels or manually assigned regions of interest (ROI). However, many sparse, small objects such as Alzheimer's disease (AD) brain deposits of amyloid peptides called plaques are neither single pixels nor ROI. Here, we propose a new approach to facilitate comparative computational evaluation of amyloid plaque-like objects by MSI: a fast PLAQUE PICKER tool that enables statistical evaluation of heterogeneous amyloid peptide composition. Comparing two AD mouse models, APP NL-G-F and APP PS1, we identified distinct heterogeneous plaque populations in the NL-G-F model, but only one class of plaques in the PS1 model. We propose quantitative metrics for the comparison of technical and biological MSI replicates. Furthermore, we reconstructed a high accuracy 3D-model of amyloid plaques in fully automated fashion, employing rigid and elastic MSI image registration using structured and plaque-unrelated reference ion images. Statistical single plaque analysis in reconstructed 3D-MSI objects revealed the Aβ1-42Arc peptide to be located either in the core of larger plaques or in small plaques without co-localization of other Aβ isoforms. In 3D, a substantially larger number of small plaques were observed than the 2D-MSI data indicated, suggesting that quantitative analysis of molecularly diverse sparsely-distributed features may benefit from 3D-reconstruction. Data are available via ProteomeXchange with identifier PXD020824.Additional experimental details and supporting figures (PDF). Animated version of MSI 3D model (AVI).

Following spatial Aβ aggregation dynamics in evolving Alzheimer’s disease pathology by imaging stable isotope labeling kinetics

“…Further, our data indicate that the A1-38 is the second main peptide present in the APP NL-G-F mice. Recently, MALDI-based three-dimensional reconstruction of amyloid plaques in aged APP NL-G-F mice suggested the presence of A1-42 in cores that were surrounded by A1-38 in most but not all plaques (28). SILK imaging provides strong evidence for a sequence of events that can explain the chemical phenotype of these plaques.…”

Imaging stable isotope labelling kinetics (iSILK) for following spatial Aβ plaque aggregation dynamics in evolving Alzheimer’s disease pathology

“…Recently, MALDI-based 3D-reconstruction of amyloid plaques in aged APP NL-G-F mice suggested the presence of Aβ1-42 in cores that were surrounded by Aβ1-38 in most but not all plaques. 20 iSILK imaging provides strong evidence for a sequence of events that can explain the chemical phenotype of these plaques. This is further in line with ELISA results for these mice 23 , where the other main peptide detected was the Aβ1-38.…”

“…injected, labeled drug candidates. 19 Most significantly, MALDI-IMS allows for chemically specific Aβ peptide imaging of Aβ pathology in animal models of AD 10, 20 and in post mortem human AD brain tissue. 21, 22…”

M2aia—Interactive, fast, and memory-efficient analysis of 2D and 3D multi-modal mass spectrometry imaging data

“…Prior to peptide MSI, tissue sections were delipidated using the washing procedure by Yang and Caprioli [ 17 ]: 70% ethanol (30 s), 100% ethanol (30 s), Carnoy fluid (60/30/10 ethanol/chloroform/acetic acid v/v/v) (120 s), 100% ethanol (30 s), ddH2O (30 s), and 100% ethanol (30 s). Peptide MSI was performed on a Rapiflex MALDI-TOF MS (Bruker Daltonics, Bremen, Germany) in positive linear mode with m / z 2,000–10,000 using FlexImaging 5.0 software (Bruker Daltonics, Bremen, Germany) as described elsewhere [ 7 ].…”

“…The emerging field of 3D MSI [ 7–10 ] offers new perspectives into the molecular structure of biological samples. Images created by 3D mass spectrometry (MS) can be generated by combining multiple adjacent 2D MS images of consecutive cuts of a biological sample to an MS image volume by co-registration (3D image reconstruction) [ 5 , 11 , 12 ].…”