# Variant-specific dynamics of amyloid-b  fibrils

> **NIH NIH R15** · UNIVERSITY OF COLORADO DENVER · 2021 · $463,077

## Abstract

One of the hallmarks of Alzheimer’s disease (AD) is the presence of neurotoxic amyloid-β (Aβ) deposits in
brain tissue. All A species from oligomers to fibrils exist in a dynamic equilibrium, which is believed to
trigger a pathological cascade implicating other aggregation-prone proteins. The so-called polymorphism of
A exists at multiple levels, from the length and molecular modifications of A to the morphological
differences within the same molecular structure, to general conformational diversities and dynamics within
a single structural unit. The post-translational modifications (PTMs) have been recently implicated in
sporadic AD onset, as they are thought to trigger or accelerate the fibrillation of the wild-type A peptide
and enhance its toxicity. Further, membrane-A interactions and the resulting aggressive
oligomeric/protofibrils mixtures are increasingly implicated in elevated cytotoxicities. The long-term goal of
our research is the correlation of the intrinsic flexibility of A species with existing structural, aggregation,
and toxicitiy studies in order to pinpoint the role of conformational ensembles in promoting more
toxic/aggressive states. Having established the main features of the intrinsic flexibility of the wild-type A
fibrils, as well as the key flexibility features of the disordered N-terminal domain of several PTMs in our
previous studies, we propose to examine which features of conformational ensembles propagate into the
cross-seeded species and what other dynamical alterations are seen compared with the self-seeded wild-
type A. The goal of the proposed work is to obtain quantitative site-specific characterizations of dynamics
in the Aβ1-40 fibrils originating from the seeded growth of several strategically chosen systems: a) seeds with
PTMs of Aβ1-40 in the N-terminal region, which have been found to enhance fibrillation kinetics and
toxicities; and b) seeds produced in the presence of high concentration of synaptic plasma membrane
vesicles from rats’ brain tissues (SV). The latter can be at least partially treated within the same paradigm
as PTMs, assuming that the interactions between the SV surface and A oligomer/protofibrils/fibrils mixtures
create unique conformational ensembles that can be considered to be a “modification” analogous in its
seeding actions to PTMs with relatively aggressive aggregation propensities. We hypothesize that a range
of dynamical features propagate from the PTMs or SV seeds to the wild-type A fibrils and that these
“conserved” features may be the most important for the correlations with aggregation propensities and
cross-seeding aggressiveness. The joint investigation of the SV-A interactions and PTM cross-seeding
imprint can advance our understanding of the relationship between the amyloid fibril polymorphism and
aggregation aggressiveness, ultimately shedding light on potentially relevant pathological features. Our
main tools are static deuterium solid-state NMR and computationa...

## Key facts

- **NIH application ID:** 10291100
- **Project number:** 2R15GM111681-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Liliya Vugmeyster
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $463,077
- **Award type:** 2
- **Project period:** 2014-08-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10291100

## Citation

> US National Institutes of Health, RePORTER application 10291100, Variant-specific dynamics of amyloid-b  fibrils (2R15GM111681-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10291100. Licensed CC0.

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