# A Pluripotent Stem Cell-Based Model to Investigate the Mechanisms of TBI-Induced AD

> **NIH NIH R21** · ARIZONA STATE UNIVERSITY-TEMPE CAMPUS · 2020 · $190,186

## Abstract

7. PROJECT SUMMARY ABSTRACT
Although the majority of AD patients are sporadic, several factors that increase risk or susceptibility to
developing AD-related pathology and cognitive decline have been identified. Specifically, traumatic brain injury
(TBI) has been linked to an increased susceptibility to AD and AD-related dementia many years after the initial
injury. Amyloid-dependent and -independent mechanisms have been postulated to explain the risk inducing
effect of TBI, but the molecular and cellular mechanisms by which TBI increases AD disease risk remain
unclear. Current studies to examine the link between the mechanical injury associated with TBI and
development of AD-related phenotypes have been limited to (i) rodent models, which while have provided
valuable information in understanding possible connections between TBI and AD, do not recapitulate all
aspects of the human disease and (ii) neuronal cells from cadaveric tissue samples which only provide an end-
stage view of the disease and rapidly loose disease-related phenotypes upon extensive ex vivo culture. With
hiPSC technology, it is possible to obtain a fully differentiated cell type (such as a skin cell) from an AD patient
and reprogram it back into a cell type that is capable of differentiating into all of the cell types of the mature,
adult body (such as neural cells of the cortex). Although we and others have used AD hiPSC-derived neural
cells to study this disease in a simplified and accessible system, applying hiPSC-based technologies to study
the connection between TBI-related cellular injuries and the onset of AD-related phenotypes has not yet been
achieved. To that end, we will use our collective experience in stem cell bioengineering and neurodegenerative
disease modeling to develop a highly accessible in vitro model to elucidate potential genetic, molecular, and
cellular mechanisms by TBI-induced cellular injuries lead to AD onset and age-related progression. In the first
aim of this proposal, we will validate an electro-mechanical cell-shearing model of TBI using 3-D hiPSC derived
neuronal-astrocytic co-cultures. In the second aim, subsequent phenotypic analysis of injured and uninjured 3-
D cortical cultures derived from non-demented control and AD hiPSCs will reveal the (i) direct effect of the
mechanical injury on susceptibility to AD-related toxic stimuli, (ii) potential signaling pathways and
transcriptional targets that are independently influenced by mechanical injury and disease status and (iii) effect
of mechanical insults on the manifestation or augmentation of AD-related phenotypes. Overall, the ability to
identify definitive relationships between mechanical injury and AD-related phenotypes will have a significant
translational impact on the design of molecularly targeted therapies to treat the many patients suffering from
TBI-induced AD.

## Key facts

- **NIH application ID:** 9903188
- **Project number:** 5R21AG063358-02
- **Recipient organization:** ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
- **Principal Investigator:** DAVID A BRAFMAN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $190,186
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903188

## Citation

> US National Institutes of Health, RePORTER application 9903188, A Pluripotent Stem Cell-Based Model to Investigate the Mechanisms of TBI-Induced AD (5R21AG063358-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9903188. Licensed CC0.

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