# Characterizing Alzheimer's Amyloid-beta Oligomer Structures by Solid-State NMR and Cryo-Electron Microscopy

> **NIH NIH RF1** · GEORGIA INSTITUTE OF TECHNOLOGY · 2022 · $1,623,119

## Abstract

PROJECT SUMMARY
In Alzheimer's disease (AD) research, much focus has been on oligomeric assemblies of the amyloid-β (Aβ)
peptide (a small protein). Oligomers are small nanoparticles produced by the aggregation of 50 or fewer peptide
molecules. Peptide aggregation most readily produces amyloid fibrils, and it is a mystery what prevents some
oligomers from aggregating further into fibrils. Even within oligomeric and fibrillar aggregate classes, peptide
aggregates with a range of structures have been detected. Nevertheless, structural biology methods require
stable and structurally homogeneous samples to achieve high-resolution information. To elucidate what
oligomer structures are possible and which of these structures should be targeted by AD therapies, experiments
are designed to understand Aβ assembly in general terms. Preliminary data show that it is possible to produce
stable homogeneous samples of a 150 Aβ oligomer (32 Aβ peptide molecules) and study its structure using
solid-state nuclear magnetic resonance (NMR) and electron microscopy (EM). Notably, the 150 kDa oligomer
structure is unlike any previously understood Aβ assembly, and this observation presents a unique opportunity
to probe how oligomer and fibril structures may differ. The project will pursue high-resolution atomic-level
characterization of the 150 kDa oligomer by integrating solid-state NMR, cryo-EM, and computational modeling.
The work further seeks to generalize understanding of Aβ assembly mechanisms by testing hypothesized
assembly pathways inspired by the 150 kDa oligomer. The proposed work will: achieve a 3-dimensional image
of the 150 kDa oligomer using cryo-EM (Aim 1); measure complementary atomic-level structural constraints with
solid-state NMR (Aim 2); and test mechanistic hypotheses to produce new oligomers compatible with EM and
NMR workflows (Aim 3). Knowledge of what oligomer structures are possible for Aβ (and how to isolate specific
structures) is critical for developing new Alzheimer's therapeutics, implementing strategies for early detection,
and designing mechanistic studies in disease models.

## Key facts

- **NIH application ID:** 10455850
- **Project number:** 1RF1AG073434-01A1
- **Recipient organization:** GEORGIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Anant Krishna Paravastu
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,623,119
- **Award type:** 1
- **Project period:** 2022-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455850

## Citation

> US National Institutes of Health, RePORTER application 10455850, Characterizing Alzheimer's Amyloid-beta Oligomer Structures by Solid-State NMR and Cryo-Electron Microscopy (1RF1AG073434-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10455850. Licensed CC0.

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