# Structural studies of amyloid beta globulomers with EPR spectroscopy

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $390,000

## Abstract

Project Summary/Abstract
 Alzheimer’s disease, the major cause of dementia, is a fatal neurodegenerative disorder. The primary risk
factor for Alzheimer’s disease is age. The prevalence of Alzheimer’s disease increases dramatically when
people reach 65 years or older, reaching nearly 50% for people of >85 years old. Therefore, Alzheimer’s
disease poses an enormous challenge to the healthcare system, and is a major obstacle for longevity.
Extensive scientific research has identified soluble Aβ aggregates, collectively termed “oligomers”, as the
primary neurotoxins that cause synapse dysfunction and neuronal death. Detailed structural knowledge on
these Aβ oligomers would shed light on the basis of neurotoxicity and facilitate drug development to cure
Alzheimer’s disease. Unfortunately, the progress on this front has been painfully slow. In this project, we
propose to characterize the structure of Aβ globulomers formed by the 42-residue isoform of Aβ protein. Our
preliminary studies have shown that, with electron paramagnetic resonance (EPR) spectroscopy, we were able
to resolve structural heterogeneity and reveal the antiparallel architecture in Aβ oligomers. This project will
build upon these preliminary studies and further tackle four specific aims. First, we will study the detailed
secondary structure of Aβ42 globulomers using spin label mobility analysis at all 42 residue positions. Second,
we will characterize the tertiary structure using intra-molecular distance measurements. Third, we will
characterize the quaternary structure through inter-molecular distance analysis. Fourth, we will use protein
structure prediction program Rosetta to model the structure of Aβ42 globulomers and cross-validate the top
models using mutagenesis approaches. The field of Alzheimer’s research has suffered from a lack of accurate
structural models of Aβ oligomers. Success in this project will fill this gap and provide unprecedented insights
into the structures of Aβ42 oligomers. The structural knowledge on these oligomers will greatly facilitate the
overall effort in understanding and treating Alzheimer’s disease and other amyloid-involved human diseases,
including Parkinson’s, Huntington’s, and type 2 diabetes.

## Key facts

- **NIH application ID:** 9899173
- **Project number:** 5R01AG050687-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Zhefeng Guo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2017-07-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899173

## Citation

> US National Institutes of Health, RePORTER application 9899173, Structural studies of amyloid beta globulomers with EPR spectroscopy (5R01AG050687-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899173. Licensed CC0.

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