# Local and global consequences of hyperphosphorylated tau in the locus coeruleus in Alzheimer's Disease

> **NIH NIH F31** · EMORY UNIVERSITY · 2022 · $46,752

## Abstract

PROJECT SUMMARY
 Alzheimer’s disease (AD) is the most common form of dementia world-wide, afflicting nearly 46 million
people. The two hallmark AD pathologies are extracellular β-amyloid (Aβ) plaques and intracellular aggregated
tau, termed neurofibrillary tangles. Many treatments that target amyloid deposition in mid to late stages of disease
are effective in animal models but have failed in clinical trials. However, recent evidence indicates that
hyperphosphorylated “pre-tangle” tau in the noradrenergic locus coeruleus (LC) appears decades prior to
cognitive symptoms and Aβ deposition, offering fresh insight into the potential cause and progression of AD. The
LC coordinates distinct brain states through norepinephrine release at target sites, and many LC-modulated
behaviors go awry in AD, but few studies have directly investigated the consequences of aberrant tau on LC
function. Aberrant tau expression causes hypoactivity in neurons, and tau load is associated with blunted novelty
response, a key behavior influenced by LC activity. Furthermore, the LC does not exhibit frank neuronal loss
until late stages of disease when cognitive decline is evident, but neuron morphology is altered, and innervation
density is decreased at early stages of disease. Despite these potentially pathogenic changes, our data indicates
that activation of the LC has the potential to restore normal cognition. In TgF344-AD transgenic rats, similar to
humans, hyperphosphorylated tau appears in the LC prior to tau or Aβ pathology in the forebrain. Importantly,
chemogenetic activation of the LC is effective at rescuing spatial learning deficits in aged TgF344-AD rats,
indicating that LC stimulation enhances cognition even in the presence of AD-like neuropathology in the LC and
forebrain. However, there is no information regarding the effects of tau on LC physiology or LC-induced changes
in brain-wide functional connectivity.
 In this proposed project, I will use TgF344-AD rats to assess both tau-mediated LC neuron dysfunction
and the therapeutic potential of LC stimulation to correct functional connectome deterioration. In Aim 1, I will use
in vivo electrophysiology to determine whether hyperphosphorylated tau in the LC can alter neuron firing rates
in an age-dependent manner. In Aim 2, I will combine optogenetic stimulation of the LC with simultaneous
functional magnetic resonance imaging to assess whether LC stimulation can rescue brain-wide network
functional connectivity deficits. I hypothesize that aberrant tau will decrease neuron firing rates in an age-
dependent manner that will be paralleled by gradual, brain-wide hypoconnectivity, which will be corrected by
optogenetic LC stimulation. Completion of these aims will determine the functional consequences of the earliest
known AD pathology, hyperphosphorylated tau in the LC, and facilitate development of LC-NE based therapeutic
interventions to retard progression.

## Key facts

- **NIH application ID:** 10457464
- **Project number:** 5F31AG069502-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Michael Kelberman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457464

## Citation

> US National Institutes of Health, RePORTER application 10457464, Local and global consequences of hyperphosphorylated tau in the locus coeruleus in Alzheimer's Disease (5F31AG069502-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10457464. Licensed CC0.

---

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