Progressive alterations in lipid distribution and composition in a murine Alzheimer’s disease model visualized by label‐free Raman microscopy

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is accompanied by severe alterations in the brain lipid profile, affecting both the type and the distribution of lipids in the tissue. Moreover, literature also suggests a close association of Aβ plaques and lipids, exacerbating amyloidogenesis and plaque deposition. Thus, a spatially resolved approach is eminently important to understand the chemical nature of the progressive relationship between Aβ plaques and surrounding lipids. In the here presented study, Raman microscopy, a label‐free, chemically selective technique, was used in combination with state‐of‐the‐art statistics to analyze Aβ plaques and the surrounding tissue in a murine Alzheimer’s disease model. By encompassing differently aged diseased and healthy mice, this study aimed to generate knowledge on the alterations of Aβ plaque surrounding lipids during disease progression, whilst advancing the application of Raman microscopy within a neurodegenerative context.MethodRegions of interest in brain sections of APP/PS1 (Amyloid‐Precursor‐Protein / Presenilin‐1) mice aged 50 days, 5 months, and 10 months, as well as healthy non‐transgenic mice were imaged using a confocal Raman microscope (WITec GmbH, Ulm, Germany). The hyperspectral Raman data sets were processed using Project 4 software (WITec GmbH, Ulm, Germany), in‐house written Matlab scripts (The Mathworks, Inc., Natick, USA) and the Matlab‐integrated RamanLight App.ResultUsing multivariate analysis, Raman signatures of the Aβ plaques, cell nuclei, mitochondria, and lipids were identified in the tissue, characterized, and compared to each other (Figure 1). Subsequently, the lipid signal was semi‐quantitatively analyzed. The results of this analysis indicate an increasing, massive abundance of lipids in the direct vicinity of the Aβ plaques with disease progression, and the biochemical Raman spectra also reveal the growing presence of long‐chained lipids around the Aβ plaque. Overall, a distinct shift of the lipid spectra and abundance, starting with disease manifestation, is observed in the proximity of the plaques.ConclusionThe presented study shows progressive alterations in the distribution and type of lipids surrounding Aβ plaques in an AD model, spatially resolving lipid alterations and providing valuable additional biochemical insight to more established imaging methods such as fluorescence microscopy.