# Determining How Amyloid-β Fibril Polymorphism Influences Cellular Toxicity

> **NIH NIH P20** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2024 · $268,948

## Abstract

As with Alzheimer’s Disease (AD), the pathological hallmark of Cerebral Amyloid Angiopathy (CAA) is the 
formation of plaques composed of amyloid-β (Aβ) fibrils. It is widely hypothesized that structural variants of 
fibrils, termed polymorphs, contribute to the pathophysiology of CAA and AD. However, there is no clear 
understanding of how their molecular structure induces cytotoxic activity. The objective of this application 
is to employ novel chemical imaging and electrochemical sensing methods to directly monitor the structural 
dynamics, aberrant interactions, and toxic activities of different Aβ fibril polymorphs. The central 
hypothesis is that toxic polymorphs promote cytotoxicity by exhibiting faster growth kinetics, disrupting 
cellular membranes, and inducing higher levels of oxidative stress via reactive oxidative species (ROS) 
generation. This hypothesis will be tested by pursuing three specific aims: 1) Characterize the molecular 
structures and growth mechanisms of Aβ fibrils using Raman spectroscopy; 2) Employ novel stimulated 
Raman chemical imaging methods to directly visualize the interactions between Aβ fibril polymorphs and 
living cells; and 3) Use electrochemical sensing to directly assess levels of reactive oxygen species (ROS) 
induced by Aβ fibril polymorphs. Under Aims 1 and 2, a novel methodology pioneered by the Punihaole 
group called Raman Chemical Imaging, will be used to directly monitor how different fibril polymorphs grow, 
structurally evolve, and alter the fluidity, integrity, and chemical composition of cellular membranes. In Aim 
3, oxidative stress induced by different fibril polymorphs will be monitored. This will be accomplished using 
fast electrochemical measurements to measure acute and chronic changes in the concentration of ROS 
generated by the cells. Synergistic coupling of these novel methods is innovative since they together 
provide structural and chemical information on time scales required to link molecular-level interactions 
between fibril polymorphs and cellular components with cellular responses, including the production of 
ROS and rapid release of cytotoxic markers. The proposed work is significant because it builds the 
foundation of a broader research program that will produce a holistic understanding of how the molecular 
structure of amyloid fibrils underlies the pathophysiology and clinical symptoms of patients with CAA and 
AD. Ultimately, the insights obtained will guide treatment strategies and the rational design of drugs to 
limit the formation of toxic strains of Aβ fibrils, inhibit their aberrant interactions with cells, mitigate oxidative 
damage, and potentially reverse the loss of cortical tissue and atrophy associated with dementia.

## Key facts

- **NIH application ID:** 11000249
- **Project number:** 5P20GM135007-05
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** MARK T NELSON
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $268,948
- **Award type:** 5
- **Project period:** 2020-08-06 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11000249

## Citation

> US National Institutes of Health, RePORTER application 11000249, Determining How Amyloid-β Fibril Polymorphism Influences Cellular Toxicity (5P20GM135007-05). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/11000249. Licensed CC0.

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