# Impact of locus coeruleus-derived tau pathology in a rodent model of early Alzheimer's disease

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $462,811

## Abstract

Amyloid-β (Aβ) plaques and tau neurofibrillary tangles, as well as neuronal death, are the pathologic hallmarks
of Alzheimer's disease (AD). Therapeutic efforts focused on Aβ have thus far failed, underscoring the urgent
need for alternate approaches, particularly those that can target early AD. Aberrant tau in the locus coeruleus
(LC), the major noradrenergic nucleus in the brain that regulates attention, arousal, stress responses, and
cognition, is the earliest detectable AD-like neuropathology in the human brain, and LC degeneration is
ubiquitious in later AD. Recent research indicates that early LC dysfunction may contribute to prodromal AD
symptoms such as depression, anxiety, and sleep disorders, while later LC degeneration exacerbates cognitive
impairment. Although these data suggest that the LC is a promising therapeutic target in AD, almost nothing
known about how pathogenic tau impacts LC function and survival. We have developed a viral vector that
drives the expression of wild-type human tau exclusively in LC neurons, which over time becomes
hyperphosphorylated and misfolded, thus recapitulating the earliest forms of human AD. We will use this novel
tool to study the consequences tau pathology in the LC. In Aim 1, we will determine the impact of different
forms of aberrant tau on LC neuron morphology, survival, and local inflammation, and assess the potential of
LC-derived tau pathology to spread to interconnected forebrain regions. In Aim 2, we will use in vivo
electrophysiology and behavioral paradigms to evaluate how tau pathology affects LC activity and performance
in neuropsychiatric and cognitive domains. In Aim 3, we will combine optogenetics and fMRI to determine how
aberrant tau influences LC-forebrain functional connectivity. Completion of these aims will lay the groundwork
for LC/tau-based therapies for early AD.

## Key facts

- **NIH application ID:** 10764294
- **Project number:** 5R01AG062581-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Shella D Keilholz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $462,811
- **Award type:** 5
- **Project period:** 2020-04-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764294

## Citation

> US National Institutes of Health, RePORTER application 10764294, Impact of locus coeruleus-derived tau pathology in a rodent model of early Alzheimer's disease (5R01AG062581-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10764294. Licensed CC0.

---

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