# REPURPOSING PRION PROTEINS AS TRANSLATIONAL AMYLOID-TARGETING THERAPEUTICS FOR ALZHEIMER'S DISEASE

> **NIH NIH K01** · YALE UNIVERSITY · 2020 · $126,505

## Abstract

PROJECT SUMMARY
 Cognitive decline in Alzheimer’s Disease (AD) and many other age-related dementias have long been
associated with the presence of insoluble amyloid plaques that disrupt normal synaptic functioning. However,
more recent studies have revealed that synapse impairment from AD is much more potently associated with
soluble amyloid-beta oligomers (abo), rather than from insoluble fibrils. Soluble oligomers are structurally
irregular and promiscuously bind to membrane proteins, thereby dysregulating downstream amyloid assemblies
such as tau. These properties, unfortunately, have also made it difficult to experimentally characterize abo, since
oligomeric states can be transient or otherwise observed as noise.
 Multiple genome-wide screening methods have identified cellular prion protein (PrPc) as a putative target
of abo, and subsequent studies have confirmed a pathophysiological pathway in AD involving abo-PrPc binding.
Interestingly, ab monomers and insoluble fibrils do not bind to PrPc, thus the binding domain of PrPc can be
exploited in peptide aptamers to target and stabilize abo. Here, we seek to utilize these interactions by designing
biomimetic PrPc peptides that complex soluble abo. Molecular simulations and amyloid-characterizing
experiments will be combined to optimize aptamer-abo interactions in order to abrogate binding of abo to PrPc.
While aptamers are unlikely to serve as an AD therapeutic, amyloid-targeting PrPc peptides can guide the
construction of next-generation agents that cross the blood-brain barrier and potently inhibit the toxicity of abo.
Similarly, identification of abo by aptamers can potentially enable the tracking of soluble oligomers through
fluorescent tagging during the formation of insoluble fibrils. Given that there are few, if any methodologies to
target abo, this proposal would seek to isolate soluble oligomers and identify the limitations of their interactions
with membrane proteins.
 In order to synergistically combine molecular dynamics simulations with experiments, mentoring will be
carried out on the use of NMR spectroscopy, chromatography, and ligand-binding assays to measure oligomer
structure, size, and the ability to bind PrP proteins, respectively. Mentoring will include regular meetings,
coursework, workshops, and immersion in the laboratory of the primary mentor. Additionally, this study will seek
to bridge basic biophysical research with clinically-relevant systems through the translation of model aptamers
from simulations into experiments. Results will be connected to and interpreted in the context of Alzheimer’s
Disease. The protocols and products developed as a result of this study will subsequently inform follow-up
studies of soluble amyloid toxicity in live cells, with extensions to multiple neurodegenerative diseases.

## Key facts

- **NIH application ID:** 9891697
- **Project number:** 1K01AG062752-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Zachary Alan Levine
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $126,505
- **Award type:** 1
- **Project period:** 2020-06-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891697

## Citation

> US National Institutes of Health, RePORTER application 9891697, REPURPOSING PRION PROTEINS AS TRANSLATIONAL AMYLOID-TARGETING THERAPEUTICS FOR ALZHEIMER'S DISEASE (1K01AG062752-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9891697. Licensed CC0.

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