# Structural and Biological Characterization of Diverse Oligomers Derived from Abeta

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2024 · $48,351

## Abstract

Project Summary/Abstract: This supplement to AG072587 seeks funding for an under-represented
minority (URM) graduate student researcher (GSR) to perform additional studies directed toward Aim 1 of the
parent grant and to receive training and mentorship in support of her path to becoming a Ph.D. biomedical
research scientist.
 The parent grant seeks to understand the aggregation of the β-amyloid peptide (Aβ) to form toxic oligomers
in Alzheimer’s disease (AD) through the structural, biophysical, and biological profiling of a diverse group of Aβ
oligomer models and correlation of these models with biogenic Aβ oligomers. My laboratory has developed an
approach to create structurally defined Aβ oligomer models composed of peptide fragments from Aβ constrained
into a β-hairpin. We characterize these oligomer models by X-ray crystallography and then introduce chemical
crosslinks to create covalently stabilized Aβ oligomer models that mimic the crystallographic oligomers. Studying
the crosslinked oligomers then allows detailed correlation between oligomer structure and biophysical and
biological properties.
 Aim 1 of AG072587 seeks to characterize the relationship between Aβ oligomer model structure, assembly,
and biology. In this Aim, we characterize how our Aβ oligomer models interact with neurons and other brain cell
types to shed light on the relationship between Aβ oligomer structure and cellular events that occur in AD. We
also elucidate the relationship between the structures of our Aβ oligomer models and biogenic Aβ oligomers, by
generating polyclonal antibodies against the Aβ oligomer models and then examining the immunoreactivity of
these antibodies with brain protein extract and brain slices from 5XFAD mice.
 Aim 2 of AG072587 seeks to discover new Aβ oligomer models, by creating new Aβ β-hairpin peptides that
contain more of the Aβ peptide sequence and alternate β-strand alignments. We are creating new crosslinked
Aβ oligomer models by identifying key contacts in existing and newly discovered Aβ oligomer models and then
engineering in disulfide bonds to stabilize the oligomers. To characterize the structures and oligomerization
properties of the new Aβ oligomer models that we generate, we are using X-ray crystallography and a variety of
other biophysical experiments. We then characterize biological and immunological properties of these new Aβ
oligomer models as outlined in Aim 1.
 Under the support of the supplement, the URM GSR will develop an approach to allow the creation of mouse
polyclonal antibodies against our Aβ oligomer models in order to amplify the impact of Aim 1, which currently
only uses rabbit polyclonal antibodies. By expanding Aim 1 to mouse polyclonal antibodies, we will lay the
groundwork for creating mouse monoclonal antibodies and their investigation as potential therapies in mouse
models for Alzheimer’s disease. The URM GSR plans to investigate this in a subsequent F31 diversity fellowship.

## Key facts

- **NIH application ID:** 11082544
- **Project number:** 3R01AG072587-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** JAMES S NOWICK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,351
- **Award type:** 3
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11082544

## Citation

> US National Institutes of Health, RePORTER application 11082544, Structural and Biological Characterization of Diverse Oligomers Derived from Abeta (3R01AG072587-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11082544. Licensed CC0.

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