# A human organoid approach to understanding the role of the locus coeruleus in Alzheimer's disease

> **NIH NIH F32** · EMORY UNIVERSITY · 2024 · $73,828

## Abstract

PROJECT SUMMARY
Alzheimer’s disease (AD) is the most common form of dementia and affects over 6 million Americans. There is
no cure for AD, and many potential treatments have failed, creating a critical need for the development of
additional disease models for novel therapeutic discovery and testing. The hallmark pathology of AD includes
amyloid-β (Aβ) plaques and hyperphosphorylated tau (ptau)-containing neurofibrillary tangles. This pathology is
associated with memory loss, which is diagnostic for AD, but is now known to be preceded by earlier prodromal
symptoms including mood and sleep disorders. Dysregulation of the neurotransmitter norepinephrine (NE) is
associated with AD symptoms, as its release in the forebrain regulates attention, arousal, stress response, and
learning and memory. Importantly, the locus coeruleus (LC), the main noradrenergic nucleus in the brain and
source of NE in the forebrain, is the first brain region to develop ptau inclusions, may transmit pathogenic tau to
the forebrain, and undergoes catastrophic degeneration in later stages of the disease. Recent evidence indicates
that that early ptau-mediated LC dysfunction contributes to the prodromal symptoms of AD, while LC neuronal
loss later in the disease exacerbates cognitive impairment. However, nearly all information about the LC in AD
has been derived from rodent models and postmortem or human imaging studies. It is not known how the early
ptau accumulation in the human LC affects neuronal function or NE transmission. Organoids, which are 3D
human cell culture models derived from human induced pluripotent stem cells, emulate the architecture and
function of human tissue. The goal of this proposal is to develop the first human LC organoid model to address
questions related to the earliest stages of AD. In Aim 1, I will validate our LC organoids by comparing their
structure and function to human and rodent LC neurons. I will then combine LC organoids with cortical organoids
to define assembloid connectivity by tracking NE innervation of the cortical organoids. In Aim 2, I will derive LC
organoids from AD patients and compare their structure, function, and AD pathology to that of LC organoids
derived from healthy subjects. Following LC-cortical assembloid creation, I will assess the consequences of NE
AD pathology transmission from AD LC organoids to control cortical organoids. Together, the proposed
experiments will provide new insights on AD pathology and normal and AD LC-cortex connectivity in living human
neurons. This information would greatly impact AD research and provides a novel model for the development of
new treatment strategies for patients in the earliest stages of AD.

## Key facts

- **NIH application ID:** 10997894
- **Project number:** 1F32AG090054-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Margaret Tish
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $73,828
- **Award type:** 1
- **Project period:** 2024-09-30 → 2025-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997894

## Citation

> US National Institutes of Health, RePORTER application 10997894, A human organoid approach to understanding the role of the locus coeruleus in Alzheimer's disease (1F32AG090054-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10997894. Licensed CC0.

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