# Exploiting Alzheimer's disease patient-derived stem cells to biochemically define tau and amyloid-beta oligomer toxic features and their downstream cellular effects

> **NIH NIH R01** · WESLEYAN UNIVERSITY · 2022 · $328,600

## Abstract

Project Summary:
Alzheimer's disease (AD) is an ever-growing socio-economic burden across the globe. Oligomerized amyloid-b
peptide (Ab) and hyper-phosphorylated tau are the pathological hallmarks of the disease and a key piece of the
neurodegenerative cascade that leads to symptoms. To develop effective oligomer targeting therapies, we must
fully describe the biochemical attributes of the target. The objective of this grant is to link oligomer structural
components to toxic bioactivity and delineate the steps in the AD neurodegenerative cascade. The central
hypothesis is that by using AD patient derived induced pluripotent stem cells (iPSC) cultured as cerebrocortical
organoids, we can recreate the AD niche closely enough to produce brain-like Ab and tau oligomers and to
understand cell type specific responses to oligomer exposure. Our rationale is that the cell type in which a protein
is made heavily impacts its function and so to fully recapitulate AD in vitro, you must model the human brain.
Our AD patient derived iPSC model will capture the important genetic and tissue specific elements to support
Ab/tau oligomerization and intercellular communication networks. Our specific aims will test the following
hypotheses: (Aim 1) AD patient iPSC grown as cerebrocortical organoids recreate the AD niche and produce
bioactive Ab and tau oligomers; (Aim 2) Through toxicity screening on iPSC derived neurons and glia
independently, we will discover the primary and secondary cellular responders to Ab and tau oligomer exposure;
(Aim 3) Not every cell is exposed to Ab and tau oligomers directly and yet there is wide spread degeneration.
Subpopulation oligomer exposure in an AD-organoid will uncover the intercellular communication networks
that causes this phenomenon. Upon conclusion, we will understand the structural components that make Ab and
tau oligomers bioactive, what the main oligomer responding cell types are, and how intercellular communication
upon oligomer exposure of some cells, effects all the cells in the niche. This contribution is significant because a
new, reliable, and relevant source of Ab and tau oligomers is needed by the community for large scale studies.
Currently used post-mortem brain tissue is scarce and due to the high lipid content, difficult to use as a source
material. Further, by biochemically defining a bioactive Ab and tau oligomer, therapeutics can be designed to
specifically target it. This research will also establish which cell types in the disease niche are the primary and
secondary responders to Ab and tau oligomers. By examining oligomer response in both stem cell derived brain
cell types in isolation and in the organoid niche, we will establish the steps in the neurotoxic AD cascade. The
proposed research is innovative because we will illustrate a new use for patient derived stem cells as a reliable
source for bioactive oligomers. This finding can be extrapolated to other diseases such as Parkinson's disease
and its r...

## Key facts

- **NIH application ID:** 10496933
- **Project number:** 1R01AG078187-01
- **Recipient organization:** WESLEYAN UNIVERSITY
- **Principal Investigator:** Alison Linsley O'Neil
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $328,600
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10496933

## Citation

> US National Institutes of Health, RePORTER application 10496933, Exploiting Alzheimer's disease patient-derived stem cells to biochemically define tau and amyloid-beta oligomer toxic features and their downstream cellular effects (1R01AG078187-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10496933. Licensed CC0.

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