# Contribution of neuromelanin to selective vulnerability of locus coeruleus neurons in Alzheimer's disease

> **NIH NIH RF1** · EMORY UNIVERSITY · 2022 · $1,531,573

## Abstract

Project Summary
Alzheimer’s disease (AD) is the most common form of neurodegenerative disease and the leading cause of
dementia, affecting over 6 million Americans. While the pathological hallmarks of AD include β-amyloid
plaques and tau neurofibrillary tangles, the appearance of hyperphosphorylated (“pretangle”) tau in the
noradrenergic locus coeruleus (LC) and loss of LC volume are the first detectable AD-like changes in the
human brain, and coincide with the onset of prodromal AD symptoms such as including arousal/sleep
disturbances, anxiety, depression, and agitation prior to frank cognitive impairment. Catastrophic LC
degeneration is ubiquitous later in disease when memory loss is evident. The goal of this proposal is to answer
two critical questions in the AD field: (1) Why are LC neurons vulnerable to developing pathology and dying in
AD, and (2) how does their dysfunction and degeneration contribute to prodromal and cognitive symptoms.
Catecholamine neurons, including the LC, are unique in their expression of neuromelanin (NM), a pigment
comprised of catecholamine metabolites, heavy metals, lipids, and protein aggregates. NM is an important
biomarker of LC neurons in AD, as NM-sensitive MRI contrast is used as a proxy of LC integrity. However,
because NM is not naturally produced in rodents, we know very little about how it might make neurons
vulnerable in AD. We have developed a viral vector expressing human tyrosinase (hTyr), which drives NM
production in the mouse LC. In Aim 1, we will determine how NM affects LC integrity. In Aim 2, we will assess
LC firing and gene expression alterations induced by NM, and how these changes in LC function trigger
behaviors relevant to prodromal and cognitive symptoms of AD. In Aim 3, we will manipulate various aspects
of NE synthesis/metabolism and tau to identify modifiers of NM accumulation and toxicity. Completion of
these aims will test, for the first time, causal relationships between NM and LC degeneration and function,
laying the foundation for novel therapies that prevent LC cell loss and behavioral and cognitive deficits in AD.

## Key facts

- **NIH application ID:** 10525513
- **Project number:** 1RF1AG079199-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** DAVID WEINSHENKER
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,531,573
- **Award type:** 1
- **Project period:** 2022-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525513

## Citation

> US National Institutes of Health, RePORTER application 10525513, Contribution of neuromelanin to selective vulnerability of locus coeruleus neurons in Alzheimer's disease (1RF1AG079199-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10525513. Licensed CC0.

---

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