# Role of the N-terminal Region in Abeta Oligomer and Fibril Formation

> **NIH NIH R15** · FLORIDA ATLANTIC UNIVERSITY · 2020 · $444,434

## Abstract

PROJECT SUMMARY
The pathogenesis of Alzheimer’s disease (AD) is characterized by the accumulation and amyloid fibril
formation of amyloid-β (Aβ) peptides in the brain. This renewal application proposes to continue our research
in the current grant period towards understanding the mechanistic roles of the dynamic and charge-rich N-
terminal region of Aβ peptide in Aβ amyloidogenesis. In the new grant period, we propose to expand our
systematic N-terminal mutagenesis approaches, and delve into the roles of the N-terminal residues,
including those involved in mutagenesis in familial Alzheimer’s disease (FAD), in regulating the microscopic
mechanisms of the rate-limiting nucleation process along the aggregation pathway. Importantly, the renewal
project will be extended to elucidate the effect of the N-terminus in modulating Aβ oligomerization and
fibrillization under the conditions that mimic the in vivo environment. Our central hypothesis is that the flexible
and hydrophilic N-terminal region of Aβ is crucial for driving the interactions of the peptide with lipid
membrane structures and polyelectrolytes that exist ubiquitously in the brain. We will identify the N-terminal
key residues and critical interactions that may play dominating roles in determining Aβ–membrane binding
kinetics and thermodynamics, membrane-templated aggregation, Aβ-induced membrane permeabilization
and disruption, and Aβ cellular toxicity. An unnatural amino acid p-cyanophenylalanine, which has been
successfully employed to identify the local dynamics in Aβ aggregation in the current grant cycle, will be
further applied to elucidate the residue-specific dynamics of membrane adsorption and insertion of Aβ
peptide. The mechanistic roles of the N-terminus in mediating polyelectrolyte-regulated Aβ aggregation and
membrane disruption will also be dissected. The outcome of the proposed research will provide novel insight
into the underlying mechanistic function of the dynamic N-terminal region in modulating Aβ aggregation
pathway, shedding light on the mechanisms of Aβ amyloidogenesis in vivo and the origin of Aβ pathology
in AD. The knowledge from this research may also allow the identification of potential molecular targets,
such as the N-terminal key residues and crucial interactions, for design of strategies to manipulate Aβ self-
assembly in vivo, which could illuminate the development of new therapeutic treatment for AD.

## Key facts

- **NIH application ID:** 9880482
- **Project number:** 2R15GM116006-02
- **Recipient organization:** FLORIDA ATLANTIC UNIVERSITY
- **Principal Investigator:** Deguo Du
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $444,434
- **Award type:** 2
- **Project period:** 2015-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880482

## Citation

> US National Institutes of Health, RePORTER application 9880482, Role of the N-terminal Region in Abeta Oligomer and Fibril Formation (2R15GM116006-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9880482. Licensed CC0.

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