# Membrane interaction and disruption by the Alzheimer's amyloid-beta peptide

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $405,851

## Abstract

Abstract
Alzheimer's disease (AD) is a neurodegenerative condition that currently affects more than 5 million
Americans. AD is characterized by decreasing memory, loss of cognitive function and an eventual reduction in
brain mass. The disease state can be linked to the cleavage of the amyloid precursor protein into smaller
fragments - amyloidogenic peptides known as amyloid-β (Aβ). In fact, the formation of amyloid fibrils of the
two most common alloforms of Aβ, Aβ1-40 and Aβ1-42, had previously been associated with disease pathology;
however, mounting evidence points to misfolded intermediates being responsible for cell death in the
Alzheimer's brain. There are a number of theories as to how Aβ elicits toxicity including the generation of free
radicals, interaction with metal ions, activation of cell surface receptors, and the disruption of cell membrane
integrity. The interaction of Aβ with the cellular membrane is especially significant given the ability of lipid- Aβ
interactions to accelerate fibril formation, facilitate the formation of ion channel-like pores, and cause the
fragmentation of the lipid membrane. While understanding and characterizing the formation of misfolded
intermediates of Aβ in solution is very important (and ongoing), the interaction of Aβ peptides with the
membrane has remained elusive and controversial. A lack of data surrounding Aβ-membrane studies is largely
due to the difficulties associated with carrying out biochemical and biophysical studies in the presence of lipids,
although much insight has been gained by molecular dynamics simulations which have provided a strong basis
for experimental studies. In order to determine the mode of membrane-associated toxicity, there remains a
need to further characterize the interactions of Aβ with the lipid membrane, determine how these interactions
drive membrane disruption, and define the structures formed in the presence of the membrane. Therefore, we
propose to investigate the membrane interaction of Aβ through the following aims: 1) Characterization of Aβ
misfolding and aggregation in the presence of lipid membranes; 2) Atomistic resolution structure determination
of Aβ in a membrane environment by solid-state NMR spectroscopy. In addition to a variety of biophysical
experiments, a combination of solution and solid-state NMR techniques and molecular dynamics simulations
will be used to successfully accomplish the goals of the proposed study. High-resolution insights gained from
the proposed studies will guide the development of drugs to stop the neuronal death. Although the proposed
study is focused on Aβ, the outcome will be of importance to other amyloid-linked diseases such as
Parkinson's disease and Type II diabetes which have similar proteinopathies.

## Key facts

- **NIH application ID:** 9896738
- **Project number:** 5R01AG048934-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Ayyalusamy Ramamoorthy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,851
- **Award type:** 5
- **Project period:** 2016-08-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896738

## Citation

> US National Institutes of Health, RePORTER application 9896738, Membrane interaction and disruption by the Alzheimer's amyloid-beta peptide (5R01AG048934-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9896738. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*