# Conformational heterogeneity and alpha-sheet: Determinants of toxicity in Abeta variants

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $672,410

## Abstract

Amyloid diseases involve conformational changes and aggregation of normally soluble peptides and proteins.
As these proteins change begin to misfold and aggregate they pass through a toxic soluble oligomer stage and
then they ultimately form insoluble fibrils. We have spent many years characterizing the early events in this
progression, and have observed a common structure form among multiple amyloid-associated peptides and
proteins despite distinct primary and tertiary structure. The structure we “discovered”, which we call α-sheet,
while rare in normal proteins, has been observed experimentally, and short stretches of α-strand are present in
the Protein Data Bank. We embarked on an endeavor to design and evaluate small peptides with complementary structures, also α-sheets, and their ability to inhibit amyloid formation in these systems. These de novo designed peptides inhibit the aggregation of multiple unrelated amyloid systems, indicating that we are targeting a generic structure. When immobilized, these designs also selectively bind the toxic oligomeric forms of these amyloid proteins over the monomers or fibrils. Here we propose to extend these studies by investigating whether α-sheet forms during amyloidogenesis of Abeta variants associated with Alzheimer's disease. The effects of targeting the toxic oligomers with de novo α-sheet designs will then be evaluated in vitro, in neuroblastoma cells, and in different, more biologically relevant systems.

## Key facts

- **NIH application ID:** 10144923
- **Project number:** 5R01AG067476-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** VALERIE D DAGGETT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $672,410
- **Award type:** 5
- **Project period:** 2020-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144923

## Citation

> US National Institutes of Health, RePORTER application 10144923, Conformational heterogeneity and alpha-sheet: Determinants of toxicity in Abeta variants (5R01AG067476-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10144923. Licensed CC0.

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