The misfolding and aggregation of specific proteins into fibrillar amyloid deposits is the pathological hallmark of a wide class of diseases and neurodegenerative disorders, which represent a major public health concern worldwide. While it is recognized that amyloid aggregates play an active part in the molecular pathology of the disease, the exact aggregation states that causes cytotoxicity and relationship between pathogenesis and the distribution of secondary structures in amyloid aggregates is not well established.
The aim of this project is to investigate the heterogeneities in protein secondary structure in amyloid aggregates both in-vitro and ex-vivo and identify their relationship with disease progression. Our approach relies on utilizing state-of-the-art nanoscale infrared (IR) spectroscopy and confocal IR spectroscopic imaging to map protein secondary structures in amyloid deposits. We will focus on studying amyloid aggregates and their heterogeneities in Alzheimer?s disease (AD) to develop and optimize our methods, and subsequently aim to extend these strategies to investigate amyloid aggregates in other diseases such as Parkinson?s disease and Breast Cancer. The hypothesis underlying this effort is that structural heterogeneities of amyloid deposits, and not just specific fibrillar structures, are correlated with disease progression. We will utilize photothermal AFM-IR, a technique that augments IR spectroscopy with Atomic Force Microscopy, to obtain nanoscale aggregate-specific spectra. Seeded growth from tissue extracts from AD patients will enable probing the differences in aggregation pathways and structural polymorphisms associated with different disease stages. Amyloid aggregates in tissues will be investigated through confocal IR microscopy. The tissue spectral data will be analyzed to classify amyloid deposits based on their secondary structure distributions, and the correlation between distinct classes of deposits and disease stages will be explored. We further aim to integrate AFM-IR and IR microscopy and develop a spatially and spectrally adaptive IR imaging approach that will enable multiscale measurement of spectral data in tissues. The unique aspect of this approach is that it uses cutting edge technologies in spatially resolved IR spectroscopy and imaging to investigate a problem that is central to the molecular pathology of a wide range of diseases and development of therapeutic strategies.

Public Health Relevance

Misfolding and aggregation of specific proteins into fibrillar aggregates is the pathological hallmark of many diseases, but the precise relationship between molecular structure of aggregates and their heterogeneities and disease pathology is yet to be fully understood. This project aims to develop a set of experimental approaches using nanoscale infrared spectroscopy and confocal infrared imaging to investigate the heterogeneities of secondary structure in amyloid aggregates and explore their correlation with disease progression. The primary focus of this approach will be to study amyloid aggregates in Alzheimer?s disease, and the methods developed herein will be extended to study other amyloid diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZRG1)
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Sakalian, Michael
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University of Alabama in Tuscaloosa
Schools of Arts and Sciences
United States
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