# Using Chirality to Understand and Control Amyloid Beta Neuronal Uptake and Toxicity

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA CRUZ · 2022 · $372,884

## Abstract

ABSTRACT
Amyloid β (Aβ) is a believed key toxic agent of Alzheimer’s Disease (AD). To develop AD therapeutics, an
improved understanding of the mechanisms of Aβ toxicity is urgently needed. In the brain, Aβ is found mostly
in extracellular deposits that may be taken up by neurons. The purpose of this proposal is to test the central
hypothesis that neuronal Aβ uptake and toxicity are linked.
Aβ forms diverse aggregates with varied neurotoxic profiles. Little is known about how structure and aggrega-
tion state affect neuronal uptake and toxicity of Aβ. This makes it very difficult to devise strategies to block
these pathogenic processes. Efforts to determine how conformation and aggregation state of Aβ affects its’
neuronal uptake and toxicity were hampered thus far by the lack of (a) methods to produce stable samples for
structural analysis and (b) accurate tools to quantify neuronal uptake of different Aβ aggregates. Recent
chirality-based approaches of the Raskatov lab have produced a set of stabilized oligomeric and fibrillary Aβ
forms that will be used here as tools, with the goal to close this important knowledge gap. Proposed research
is cross-disciplinary and collaborative: it includes structural collaborations with Dr. Eisenberg and Dr. Tycko;
Dr. Glabe will consult on neurobiology experiments done in the Raskatov lab.
The purpose of Aim 1 is to complete the structural elucidation of racemic Aβ fibrils by ssNMR, to then use
those structural insights to devise smaller, more drug-like, oligomer-to-fibril converters, and to test the working
hypothesis that oligomer-to-fibril conversion reduces Aβ uptake into neurons, thus suppressing its toxicity. This
will be accomplished using C14-based radioquantitation tools in combination with various cell culture assays to
measure both rapid and slow toxic actions of Aβ against neurons. Aim 2 will test the working hypothesis that
the differences in toxicity between Aβ42-E22e and Aβ42-S26s are due to differences in their neuronal uptake,
and will also test the alternative hypothesis that the peptides traffic to different sub-cellular sites, and that the
differences in peptide toxicity are due to that. CryoEM structures of Aβ42-E22e and Aβ42-S26s stabilized
oligomers will be sought, to identify the structural motifs responsible for their toxicity differences. Aim 3 will test
the working hypothesis that the highly aggregation-prone, N-terminally truncated Aβ-related peptide p3
promotes oligomer-to-fibril conversion in Aβ, thus reducing Aβ uptake efficiency and making it less neurotoxic.
Successful completion will yield a quantitative link between neuronal uptake and toxicity of different Aβ forms.
It may yield the world’s first Aβ oligomer structures, as well as a structure of non-toxic Aβ fibrils. It may yield
smaller, D-peptidic Aβ oligomer-to-fibril converters to be translated to novel AD therapeutics in the future, and
it will also reveal how Aβ toxicity is suppressed by p3 addition. Finally, the prop...

## Key facts

- **NIH application ID:** 10337910
- **Project number:** 1R01AG074954-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA CRUZ
- **Principal Investigator:** Jevgenij Raskatov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $372,884
- **Award type:** 1
- **Project period:** 2022-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10337910

## Citation

> US National Institutes of Health, RePORTER application 10337910, Using Chirality to Understand and Control Amyloid Beta Neuronal Uptake and Toxicity (1R01AG074954-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10337910. Licensed CC0.

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