Individual amyloids resolved in their native environment by optical photothermal infrared microscopy

Spatiotemporal alterations in the chemical and structural makeup of biomolecules play an essential role in the onset and progression of various diseases, including Alzheimer's Disease (AD). Early structural changes at the submicron level often occur well before disease symptoms can be recognized and before morphological changes can be detected using conventional tissue-level methodologies such as spatial proteomics, histology, or immunohistochemical staining. Consequently, there is a critical need for structure-sensitive techniques that can assess structures in their native environments such as brain tissue at subcellular resolution. Here, I present an approach to investigate spatiotemporal chemical changes amyloid structures at submicron resolution.

Using a recently established technique, the Medical Microspectroscopy Group from Lund University conducted experiments that enabled the monitoring of amyloids in the process of their formation, proliferation, and cellular damage directly within fresh ex vivo fully hydrated brain tissue slices (1,2). To assess structural changes with sub-micron precision, we employed optical photothermal infrared (O-PTIR) microspectroscopy, a technique sensitive to amyloid structures. By applying O-PTIR to freshly extracted brain tissue from AD model mice, we documented structural changes in functioning brain tissue, observing the appearance of newly formed amyloids spatially and temporally colocalized with lipid damage. Achieving time-resolved submicron in situ imaging of amyloid structures marks a significant technological advancement that opens new avenues for in-depth molecular analysis of amyloid formation within their natural environment, thus facilitating an understanding of why amyloids begin to form, accumulate, and damage the tissue.

1 Gvazava et al. J Am Chem Soc 2023:jacs.3c08854. https://doi.org/10.1021/jacs.3c08854.
2 Prater et al.. J Med Chem 2023:acs.jmedchem.2c01359. https://doi.org/10.1021/acs.jmedchem.2c01359.