# Impact of neuromelanin and Tau accumulation during aging and disease on local gene expression in the human locus coeruleus using spatially-resolved transcriptomics with protein detection

> **NIH NIH R01** · LIEBER INSTITUTE, INC. · 2024 · $867,306

## Abstract

PROJECT SUMMARY
The locus coeruleus (LC) is a small bilateral nucleus located in the dorsal pons of the brainstem, and serves as
the brain’s primary site for producing the neuromodulator norepinephrine (NE). NE-producing neurons in the
LC project to many regions of the central nervous system to modulate highly divergent functions including
cognition, arousal, and mood. The LC is one of the earliest sites of degeneration in Alzheimer’s disease (AD),
and profound loss of LC-NE neurons accelerates with disease progression. Several unique anatomical,
morphological and neurochemical properties likely contribute to vulnerability of LC-NE neurons. First, LC-NE
neurons synthesize neuromelanin (NM), a property shared by only a few cell types in the human brain. NM
accumulates with aging, and one hypothesis is that it initially protects LC-NE neurons by sequestering or
chelating neurotoxic substances. However, in late life and disease states, NM deposition may be detrimental
when it overwhelms cellular machinery, and accumulated toxins are released from degenerating cells. Second,
accumulation of phosphorylated tau (pTau), a primary AD neuropathology, is detected in the LC prior to any
other brain region. In this application, we generate transcriptomic-scale spatial maps that incorporate
localization of NM and pTau in the human LC in brain donors diagnosed with AD and contrast these
expression patterns to both middle-aged and age-matched elderly neurotypical donors. We will use the 10x
Genomics Visium Spatial Gene Expression and the Visium Spatial Proteogenomics platforms, which combine
transcriptome-wide RNA sequencing with detailed high-resolution histology and immunofluorescence imaging
to segment and quantify NM and pTau, respectively. We will computationally align adjacent tissue sections
from the same donor across platforms to determine how joint accumulation of NM and pTau during aging and
disease impacts the local tissue microenvironment in the human LC. Results will be validated and extended
using complementary in situ hybridization platforms with cellular resolution and simultaneous protein detection.
Accumulation of NM and pTau represent two key biological hypotheses underlying the vulnerability and
resiliency of LC-NE neurons to neurodegeneration in the human brain. Hence, generation of these data are
important because understanding the molecular sequelae downstream of this accumulation is critical to
develop strategies to target cells in the LC for disease treatment or prevention.

## Key facts

- **NIH application ID:** 10825956
- **Project number:** 1R01AG085933-01
- **Recipient organization:** LIEBER INSTITUTE, INC.
- **Principal Investigator:** Stephanie Carinne Hicks
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $867,306
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825956

## Citation

> US National Institutes of Health, RePORTER application 10825956, Impact of neuromelanin and Tau accumulation during aging and disease on local gene expression in the human locus coeruleus using spatially-resolved transcriptomics with protein detection (1R01AG085933-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10825956. Licensed CC0.

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