# Applying human in vitro models to understand the link between trauma and tau pathology

> **NIH NIH R21** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2023 · $457,049

## Abstract

Traumatic brain injury (TBI) is the most important environmental risk factor for Alzheimer’s disease and
Alzheimer’s disease related dementias (AD/ADRD). The TBI event may occur years before the emergence of
AD/ADRD so there is time to apply treatments. Unfortunately, no appropriate treatments exist because the
connection between TBI and AD/ADRD is poorly understood. Changes in tau proteins play an important role in
AD/ADRD. Calcium overload drives changes in tau. Calcium overload is also a consequence of TBI. This
proposal hypothesizes that TBI causes calcium overload that leads to tau changes and this sequence helps
explain why TBI increases the risk of AD/ADRD. Piezo1 is a calcium channel that opens when cells deform.
Therefore, it could be opened by trauma. This proposal will test this hypothesis in cortical astrocytes, cortical
neurons, and endothelial cells. These cells will be generated from human induced pluripotent stem cells. The
first Aim will measure how vulnerable each cell type is to trauma. The cells will be deformed in the same way
they are during a TBI event and resulting cell death and cell damage will be measured. Calcium overload and
inflammatory signaling will also be quantified. In patient brains, tau changes accumulate around blood vessels
after TBI but it is not clear if this pattern reflects the toxic influence of blood or the endothelial cells that line
blood vessels. Therefore, the influence of endothelial cells on neighboring astrocytes and neurons will be
measured with experiments that either mix cells in culture or transfer cell culture media between cell cultures.
Experiments with trauma-sensitive outcomes will be repeated after Piezo1 has been eliminated from the cells
to determine if Piezo1 is required for a trauma response. In addition, the same outcomes will be measured in
experiments that activate Piezo1 chemically without trauma. The second Aim will employ brain organoids.
These are clusters of brain cells that are approximately round and about 1 millimeter wide. They contain
cortical neurons and astrocytes and, in some cases, endothelial cells will be added to them. These organoids
can reproduce the calcium overload-dependent tau changes that are hypothesized to drive disease in post-TBI
AD/ADRD. They will be mechanically deformed in the same way they would be deformed during a TBI event.
Resulting cell death and cell damage will be quantified. Secretion of proteins known to indicate brain damage
and changes in spontaneous electrical activity will also be measured. In addition, total tau protein and
phosphorylated tau protein will be quantified after trauma. Microscopic imaging will determine if tau changes
accumulate around endothelial cells when they are present. As before, experiments that show sensitivity to
trauma will be repeated after Piezo1 has been eliminated from the cells. Then, they will be repeated when
Piezo1 has been activated chemically without trauma. In combination, these experiments will re...

## Key facts

- **NIH application ID:** 10786930
- **Project number:** 1R21NS135179-01
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** John D Finan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $457,049
- **Award type:** 1
- **Project period:** 2023-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10786930

## Citation

> US National Institutes of Health, RePORTER application 10786930, Applying human in vitro models to understand the link between trauma and tau pathology (1R21NS135179-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10786930. Licensed CC0.

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