# Investigating structural heterogeneities in amyloid aggregates with multiscale infrared spectroscopic imaging

> **NIH NIH R35** · UNIVERSITY OF ALABAMA IN TUSCALOOSA · 2022 · $209,500

## Abstract

Project Summary
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. However, the precise role of amyloid aggregates in disease onset and progression is not well
established. The exact aggregation states that cause neurotoxicity and relationship between distribution of
secondary structures in amyloid aggregates and cognitive decline remains unclear. 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 spatially
resolved infrared spectroscopy, namely nanoscale infrared (IR) spectroscopy, super-resolution IR microscopy
and confocal IR spectroscopic imaging to map protein secondary structures in amyloid deposits. We aim to
integrate these three techniques and develop a spatially and spectrally adaptive IR imaging approach that will
enable multiscale measurement of spectral data in tissues. The above three techniques will be further
augmented by Raman microscopy. Taken together, this approach will offer multimodal, multiscale structural and
chemical insights on amyloid aggregates, from their distribution in tissues and chemical subtypes to structural
variations within single fibrils. 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, Breast Cancer and type-II
diabetes. 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 and photothermal IR microscopies, which will allow for identifying amyloid
deposits in tissues and then investigating individual plaques with high sub-diffraction spatial resolution. 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. 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 o...

## Key facts

- **NIH application ID:** 10582209
- **Project number:** 3R35GM138162-03S1
- **Recipient organization:** UNIVERSITY OF ALABAMA IN TUSCALOOSA
- **Principal Investigator:** Ayanjeet Ghosh
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $209,500
- **Award type:** 3
- **Project period:** 2020-09-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10582209

## Citation

> US National Institutes of Health, RePORTER application 10582209, Investigating structural heterogeneities in amyloid aggregates with multiscale infrared spectroscopic imaging (3R35GM138162-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10582209. Licensed CC0.

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