# Using a human stem cell model of tauopathy to evaluate the effects of tau filaments on cell metabolism at a single cell level in vitro and in vivo

> **NIH NIH R21** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $445,500

## Abstract

Alzheimer's disease (AD) and AD-related dementias (ADRD) affect more than 40 million people worldwide
causing major disability in patients with an impairment of cognitive function and changes in social behavior. A
large subset of ADRD patients presents with frontotemporal lobar degeneration (FTLD) and widespread
deposition of hyperphosphorylated tau protein (p-tau; FTLD-TAU), which also accumulates in patients with AD.
Despite the high prevalence of these tauopathies, mechanisms of neurodegeneration are only partially
understood and curative treatment options still do not exist. There is growing evidence that non-cell-autonomous
mechanisms of neuronal degeneration play an important role during disease development and that neurons, glial
and inflammatory cells significantly contribute to pathologic changes in patients' brains via direct cell-cell
contacts, secreted factors and deposition of soluble and insoluble molecules within and outside cells. Important
work has shown neuron-to-neuron propagation of pathological tau protein in models of AD that significantly
contributes to neurodegeneration at sites of spread and tau accumulation. Our study sets out to determine the
effects of aggregated tau protein on the metabolism in patient neurons in a dynamic human stem cell model of
tauopathy both in vitro and in vivo. Encouraged by our preliminary data, we hypothesize that energy fuels such
as glucose, amino acids and especially fatty acids are used differently in patient neurons compared to control
(Ctrl) cells under basal conditions and when exposed to sarkosyl-insoluble tau filaments. We will use
differentiated induced pluripotent stem cells (iPSCs) carrying the AD-associated V717I (London) mutation in APP
(amyloid precursor protein, APPV717I) or the FTLD-TAU-associated N279K mutation in MAPT (MAPTN279K) as a
model for tauopathy. Phenotypes in these cells will be compared to those in isogenic Ctrl cells. We will test our
hypothesis of tau filament-mediated alteration of cellular programs and metabolic states in patient neurons in
two specific aims by applying stress assays, mass spectrometry for metabolites as well as single nucleus RNA
sequencing on neuron/neuron co-cultures and on mixed grafts 10 weeks after transplantation into the brains of
adult immunocompromised mice.

## Key facts

- **NIH application ID:** 10108648
- **Project number:** 1R21AG070414-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Gunnar Hargus
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $445,500
- **Award type:** 1
- **Project period:** 2020-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10108648

## Citation

> US National Institutes of Health, RePORTER application 10108648, Using a human stem cell model of tauopathy to evaluate the effects of tau filaments on cell metabolism at a single cell level in vitro and in vivo (1R21AG070414-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10108648. Licensed CC0.

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