Probing the lipid chemistry of neurotoxin‐induced hippocampal lesions using multimodal imaging mass spectrometry

Abstract

The environmental toxin β-N-methylamino-L-alanine (BMAA) has been causatively linked to neurodegenerative disease pathology. In a rat model, neonatal BMAA exposure resulted in selective uptake in the hippocampal formation and caused learning and memory impairments in adult animals. Moreover, high dose neonatal BMAA exposure resulted in formation of protein inclusions in the CA1 region of the adult hippocampus. However the mechanism underlying BMAA induced neuropathology remains elusive. Imaging mass spectrometry is a powerful method for spatial interrogation of biochemical distribution in biological tissue with high chemical specificity. The aim of this study was to therefore characterize the lipid microenvironment of BMAA-induced hippocampal lesions in adult rats using matrix-assisted laser desorption/ionization (MALDI) and time-of-flight SIMS (ToF-SIMS imaging). Multimodal imaging was carried out by ToF-SIMS scans of the hippocampal formation followed by whole tissue scans using MALDI imaging. Multivariate analysis was performed on the SIMS data in order to delineate the spatial biochemistry surrounding the lesions. The data show lesion-specific localization of phosphatidylcholine fragments, suggesting neuroinflammatory glial cell activation. Complementary MALDI imaging data showed increased levels of phosphoethanolamines colocalizing with the proteopathic lesions pointing to macroautophagic mechanisms associated with neurotoxin-induced protein accumulation. Multimodal IMS by means of ToF-SIMS and MALDI mass spectrometry proved to be a powerful technique for neurotoxicological research.

Imaging mass spectrometry in drug development and toxicology

“…Ultrastructural examination by transmission electron microscopy revealed intracellular deposition of abundant bundles of closely packed parallel fibrils in neurons, axons and astrocytes of the CA1. SIMS IMS and laser capture microdissection followed by LC–MS/MS showed enrichment of specific phospholipids and proteins in this brain region (Hanrieder et al 2014a, b; Karlsson et al 2015a, b). These molecular studies of BMAA-induced effects further illustrate the usefulness of combining IMS with other experimental techniques to identify target regions and investigate toxicological events.

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Mass spectrometry imaging for plant biology: a review

“…Co-registration of high-resolution optical images from histochemical staining with the acquired MSI data provides more in-depth information (tissue/cell type distribution), aiding sample interpretation. Another combination is that of MALDI and SIMS, which has been used extensively in plant and animal MSI imaging (Chughtai et al 2012 ; Hanrieder et al 2014 ; Ogrinc Potočnik et al 2014 ; Seaman et al 2014 ), where the former has been used to generate lower-resolution images across a wide area, and SIMS for very-high-resolution imaging of a smaller sub-section of the tissue. The modality need not be another MSI technique or optical imaging approach; other modalities including MRI, FT-IR and XRF could be employed to examine the underlying biology.…”

Unsupervised machine learning for exploratory data analysis in imaging mass spectrometry

“…Maximum Autocorrelation Factorization (MAF) was originally proposed by Switzer and Green (1984) as an alternative method to PCA to analyze satellite and other multivariate spatial data. MAF has been used as a multivariate analysis technique in SIMS on several occasions (Tyler, Rayal, & Castner, 2007;Henderson, Fletcher, & Vickerman, 2009;Park et al, 2009;Hanrieder et al, 2014), but has been used only sparsely in MALDI IMS, primarily in combination with other data analysis techniques (Jones et al, 2011;Balluff et al, 2015). Stone et al (2012) used the minimum noise fraction (MNF) transform, a related technique.…”