# Human Neural Organoid Modeling of Alzheimer's Disease Neuroinflammation for Drug Discovery

> **NIH NIH R43** · STEM PHARM, INC. · 2024 · $55,000

## Abstract

Project Summary/Abstract
Alzheimer’s Disease (AD) is the most prevalent neurodegenerative disease with more than 6.5
million Americans currently living with AD dementia. AD is defined by its neuropathological
hallmarks which include Aβ peptide plaque deposits, intraneuronal tau tangles and neuronal loss.
A major component of the AD process is neuroinflammation. Genome-wide association studies
(GWAS) have revealed several immune genes which are risk factors for developing late-onset
AD. Several of these AD risk genes such as SPI1 and TREM2 are highly expressed in microglia,
the brain’s resident macrophage-like population. Microglia phagocytose Aβ and play a central role
in the brain’s response to amyloid plaques and the neurodegenerative process. While pluripotent
stem cell-derived neural organoids do not typically contain immune cell populations, Stem
Pharm’s hydrogel-enabled neural organoids allow for incorporation of microglia in a reproducible,
96-well plate format amenable to screening applications. Using this technology, our preliminary
data demonstrate microglia incorporate into the neural organoids and respond appropriately to
inflammatory stimuli including Aβ oligomers and apoptotic neurons. Work in this proposal will lead
to the generation of a human AD-neuroinflammation organoid model by exposing cultures with
oligomeric Aβ and apoptotic neuronal cells to induce AD-like neuroinflammatory responses,
ultimately enabling a more biologically relevant human AD model for drug discovery applications
focused on immune modulation. Specific Aims will 1) optimize the model and establish the gene
expression signature of the microglia; 2) and incorporate microglia engineered with mutations in
the AD associated gene TREM2. Completion of these specific aims will establish a flexible
neuroinflammation model system capable of screening the effects of compounds or incorporating
microglia harboring mutant AD-associated genes. Phase II studies will seek to expand the
capabilities of the model by establishing and optimizing readouts to measure the effect of
inflammation on the neuronal cell populations and establish organoids from additional donors.
Ultimately, this work will develop commercially available, novel models of the AD inflammation
process which can serve to supplement the many rodent model systems currently available.

## Key facts

- **NIH application ID:** 11020764
- **Project number:** 3R43AG082625-01A1S1
- **Recipient organization:** STEM PHARM, INC.
- **Principal Investigator:** Connie S Lebakken
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $55,000
- **Award type:** 3
- **Project period:** 2023-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11020764

## Citation

> US National Institutes of Health, RePORTER application 11020764, Human Neural Organoid Modeling of Alzheimer's Disease Neuroinflammation for Drug Discovery (3R43AG082625-01A1S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11020764. Licensed CC0.

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