# Structural and Biological Characterization of Diverse Oligomers Derived from Abeta

> **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $1,373,106

## Abstract

Project Summary/Abstract: Understanding the aggregation of the β-amyloid peptide (Aβ) to form toxic
oligomers is fundamental to understanding the molecular basis of Alzheimer’s disease (AD). Despite decades of
research, the structures of Aβ oligomers remain a mystery, constituting a significant gap in understanding AD.
This proposal seeks to address this knowledge gap 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 for create structurally defined Aβ oligomer models composed of
peptide fragments from Aβ constrained into a β-hairpin. The X-ray crystallographic structures of these Aβ β-
hairpin peptides reveal the structures of oligomers that the peptides can form and key intermolecular contacts
that the peptides make in the oligomeric state. These contacts reveal sites that can be crosslinked 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.
 We will characterize how our Aβ oligomer models interact with and affect neurons, microglia, and astrocytes,
to provide detailed insights into how our Aβ oligomer models impact different brain cell types and thus help shed
light on the relationship between Aβ oligomer structure and cellular events that occur in AD. We will use
fluorescence microscopy and fluorescence-assisted cell sorting (FACS) to visualize and quantify the interactions
and uptake of our Aβ oligomer models with neurons, microglia, and astrocytes. We will evaluate downstream
biochemical and cellular effects elicited by Aβ oligomer models in neurons, microglia, and astrocytes and
evaluate how treatment affects apoptosis, necrosis, calcium homeostasis, endoplasmic reticulum stress,
oxidative stress, neurite length, tau phosphorylation and aggregation, and proinflammatory responses in
microglia and astrocytes. To elucidate the relationship between the structures of our Aβ oligomer models and
biogenic Aβ oligomers, we will generate polyclonal antibodies against each Aβ oligomer model and then examine
the immunoreactivity of these antibodies with brain protein extract and brain slices from 5XFAD mice.
 We will 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 will create 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 will use X-ray crystallography and a variety of other biophysical
experiments, including CD spectroscopy, SDS-PAGE, size exclusion chromatography (SEC), ana...

## Key facts

- **NIH application ID:** 10214205
- **Project number:** 1RF1AG072587-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** JAMES S NOWICK
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,373,106
- **Award type:** 1
- **Project period:** 2021-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10214205

## Citation

> US National Institutes of Health, RePORTER application 10214205, Structural and Biological Characterization of Diverse Oligomers Derived from Abeta (1RF1AG072587-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10214205. Licensed CC0.

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