# In vitro nonhuman primate model of frontotemporal dementia

> **NIH NIH F31** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $37,415

## Abstract

PROJECT SUMMARY/ABSTRACT
Frontotemporal dementia (FTD) is an Alzheimer’s disease-related dementia and is the most frequent form of
dementia in patients under 60 years old. Mutations in the MAPT gene encoding the neuronal protein tau,
including the autosomal dominant MAPT R406W missense mutation, have been linked to FTD. Induced
pluripotent stem cell (iPSC)-derived forebrain neuronal progenitor cells (NPCs) from MAPT R406W carriers have
provided insight on FTD pathology in vitro. These cells display p-tau aggregation, fragmentation, impaired
microtubule binding, and mitochondrial deficits. RNA sequencing of patient cells also revealed differentially
expressed genes involved in calcium and synaptic signaling, lysosomal function, and neuronal development.
Animal models that faithfully replicate FTD are needed to understand how neuronal cell tauopathy affects the
organism, identify biomarkers, and test candidate new therapies. At the Wisconsin National Primate Research
Center, 6 members of a family of rhesus macaques (aged 0.6 to 19 years) were identified as carriers of MAPT
R406W. Preliminary evaluation of these animals identified behavioral and imaging features that resemble the
human FTD phenotype. To take advantage of this resource, we generated iPSC lines from one male and one
female mutation carrier. Based on the phenotype of the rhesus carriers and the 99% MAPT sequence homology
between humans and rhesus, our overarching hypothesis is that rhesus iPSC-derived forebrain cortical NPCs
will mirror the tau-related phenotype and transcriptomic signatures observed in cells from human MAPT R406W
carriers. To test our hypothesis, we propose: Aim 1: To phenotypically characterize iPSC-derived forebrain
cortical NPCs from MAPT R406W+/- rhesus macaques with direct comparison to human patient cells.
Rhesus iPSCs will be CRISPR/Cas9-edited to correct the point mutation to serve as isogenic controls. Human
MAPT R406W iPSCs and their isogenic controls will be obtained from collaborators at the Tau Consortium.
Mutant and isogenic human and rhesus iPSCs will be patterned to forebrain cortical NPCs to study MAPT
R406W-related pathology in vitro. Aim 2: To compare the gene expression profiles of iPSC-derived
forebrain cortical NPCs from MAPT R406W+/- rhesus macaques and humans. Bulk cell RNA sequencing
will be performed on mutant and isogenic forebrain cortical NPCs from both species to determine if there is a
shared or divergent transcriptomic signature associated to MAPT R406W. Overall, these aims will establish the
validity of the rhesus NPCs as an in vitro model of FTD. This study is highly translational as these cells could
serve as an in vitro platform for screening novel therapies which will help reduce the number of monkeys used
for in vivo preclinical testing before human clinical trials.

## Key facts

- **NIH application ID:** 10899340
- **Project number:** 1F31AG084303-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Julia Claire Colwell
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $37,415
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899340

## Citation

> US National Institutes of Health, RePORTER application 10899340, In vitro nonhuman primate model of frontotemporal dementia (1F31AG084303-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10899340. Licensed CC0.

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