Aggregation of the amyloid beta (Aβ) protein into insoluble deposits or plaques is one of main pathological features of Alzheimer’s disease (AD), but their exact role in AD pathogenesis and onset of dementia is unclear. It now believed that soluble Aβ oligomers and not mature fibrils are the primary neurotoxic species in AD, and that oligomers and prefibrillar aggregates are the key contributors to AD pathogenesis while mature fibrils possibly represent the end point of the disease. Mature Aβ fibrils have a primarily parallel beta sheet structure, but Aβ oligomers have been shown to exhibit other secondary structures. It is also well known that all amyloid fibrils are not equivalent: Aβ fibrils are polymorphic, with variations in molecular structure associated with different morphologies of fibrils which not only exhibit different levels of neurotoxicity, but also have been shown to be associated with different stages of AD. Investigating structural ensembles of different amyloid aggregates is experimentally challenging, as current approaches for structure determination such as NMR and FTIR cannot spatially resolve spectra. Without spatial resolution, it is difficult to unequivocally attribute spectral features to specific aggregates or morphologies or determine which transient species evolve into a particular morphology. This limitation can be circumvented by a novel technique that integrates infrared spectroscopy with an atomic force microscope (AFM-IR). AFM-IR bypasses resolution limits in conventional IR microscopy by using the tip of an AFM probe to measure infrared absorption and can examine nanoscale structural details by combining the spatial resolution of AFM and the chemical resolution of infrared. AFM-IR offers the unique capability of acquiring infrared spectra that are sensitive to protein structure with nanoscale resolution, so characteristic features of individual aggregates and fibrils can be measured. AFM-IR measurements on different aggregation states of the Aβ 1-42 protein will be presented which highlight the structural heterogeneity of amyloid aggregates. Furthermore, optical implementations of spatially resolved spectroscopy that extend the infrared measurements to AD tissues will also be discussed, and heterogeneities of Aβ secondary structures in amyloid plaques as identified by infrared imaging will be presented.

Spatially resolved infrared spectroscopy of beta amyloid fibrils and prefibrillar aggregates in vitro and ex vivo

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.