# Emerging Roles of Higher-order Polyamines During Tauopathies

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $470,975

## Abstract

Collectively tauopathies including Alzheimer’s disease (AD) impact close to 6 million Americans and cost over
$200 billion in medical care. They devastate families and cause victims to lose their memory, their dignity and,
finally, their identity. Currently no disease modify agents exist for treating tauopathies, and AD and
spontaneous recovery is unknown; a diagnosis of tauopathy is a death sentence. Strategies proposed to
reduce tau burden include increasing clearance, decreasing phosphorylation or nitration, reducing aggregation,
and diminishing inflammation, among others. Arginine metabolism is poised at a critical branch-point and
serves as a precursor for nitric oxide generation from nitric oxide synthases or polyamine production from
arginase (Arg1). Our data indicates that Arg1 overexpression in a mouse model of tauopathy reduces multiple
aspects of the tau phenotype; phospho-tau deposition, Gallyas staining, hippocampal atrophy, high molecular
weight tau multimers, tau nitration, cytokine markers of inflammation, inhibitors of autophagy, and protein
kinase activation. Many of these effects can also be demonstrated in cell culture. We also show that higher-
order polyamines directly block tau aggregation and promote microtubule assembly in solution at physiological
concentrations, but acetylated polyamines fail to mimic this affect. Several distinct effects of this manipulation
could mediate these remarkable benefits of Arg1 over expression and polyamine metabolism. The goal of this
application is to better understand how polyamines contribute to the benefits of reducing the tau phenotype,
and identify other potential targets for treating tauopathies and possibly AD. Utilizing gene therapy, mouse
models of tauopathy, and knockout models we will test four aims. 1) Determine if Increased Polyamines
Diminish Tau Pathology. 2) Determine if Reduced Polyamines Enhance Tau Pathology. 3) Test if
Pharmacological Nutritional Modulation of Polyamines Regulates Tau Pathology and 4) Test if the Deletion of
SSAT Reduces Tau Pathology. Success in these aims will increase our knowledge regarding the role of
polyamines metabolism in regulating the tau phenotype. Our goal is to identify additional therapeutic targets
that could be regulated by pharmacological agents to arrest or slow the progression of the tau deposition in
humans with neurodegenerative disease.

## Key facts

- **NIH application ID:** 10224543
- **Project number:** 7R01AG054559-04
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Daniel Carl Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $470,975
- **Award type:** 7
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224543

## Citation

> US National Institutes of Health, RePORTER application 10224543, Emerging Roles of Higher-order Polyamines During Tauopathies (7R01AG054559-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10224543. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*