# Human vs. Rodent Amyloid-beta Fibrils

> **NIH NIH R21** · UNIVERSITY OF CHICAGO · 2020 · $445,500

## Abstract

We propose to compare the structures of human and rodent (mouse and naked mole
rat) amyloid-β (Aβ) fibrils using solid-state NMR. Transgenic mouse models are a mainstay of
Alzheimer’s disease research. Many of these models include overexpression of Aβ, with
various mixtures of human and endogenous mouse peptides in the different models. Although a
great deal has been learned about the structure of human Aβ fibrils, much less is known about
mouse Aβ, and species differences between rodent and human Aβ aggregates is
underappreciated. This difference, however, could bear importantly on studies of neurotoxicity
of Aβ. Some transgenic mouse models include massive overexpression of Aβ, and while this
leads to some cognitive impairment, the burden of amyloid deposition seems disproportionately
great compared to the neurological findings. There are several possible, non-mutually exclusive
explanations for this discrepancy. Here, we propose to study one of them: that mouse and
rodent Aβ aggregates differ structurally. It has been amply demonstrated that human Aβ
peptides display polymorphism: that is, a single polypeptide can form different fibril structures
depending on fibrillization conditions. These polymorphs differ in cyto-/neurotoxicity. Thus, this
proposal is guided by the hypothesis that structural differences in mouse and human Aβ
aggregates could lead to differences in neurological effects. As a first step in testing this
hypothesis, we will compare human and rodent Aβ40 and Aβ42 fibrils. The proposal has two
Specific Aims. The first is to compare the structures of Aβ fibrils from mouse, naked mole rat
and human peptides using SS-NMR. These peptides differ at several key residues in the N-
terminal domain of Aβ. Preliminary data (TEM, NMR) indicate that fibrils from these 3 species
(rationale for these choices is given in the proposal), formed under rigorous controlled, identical
conditions, adopt different structures. Aim 1 will continue these investigations. The second
specific aim is to study and compare the structures of mouse and human brain-seeded Aβ
fibrils. We have published several papers on producing “replicate fibrils” for solid-state NMR, by
seeding with authentic human brain amyloid from patients who died with Alzheimer's disease.
We now propose to apply these methods to compare human and mouse brain amyloid-seeded
Aβ40 and Aβ42 fibrils. Future plans are 1) to extend this work, in an R01 application, to a
comparison of the cyto-/neurotoxicity of polymorphs directly; and 2) an application of these
seeding techniques to examine brain amyloid-seeded soluble oligomers of Aβ peptides.

## Key facts

- **NIH application ID:** 9955764
- **Project number:** 1R21AG067036-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Stephen C. Meredith
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $445,500
- **Award type:** 1
- **Project period:** 2020-05-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955764

## Citation

> US National Institutes of Health, RePORTER application 9955764, Human vs. Rodent Amyloid-beta Fibrils (1R21AG067036-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9955764. Licensed CC0.

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