# Functions of Tau protein in human neural cells

> **NIH NIH R21** · UNIVERSITY OF WASHINGTON · 2024 · $208,625

## Abstract

Project Summary/Abstract
Tau protein, encoded by the MAPT gene, is a neuronally enriched protein with an established role as a
microtubule-binding protein. Abnormal accumulation of tau protein is a neuropathological hallmark of several
neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Dominant
mutations in the MAPT gene are present in inherited FTD, indicating that tau is causal in neurodegenerative
disease. However, whether these mutations lead to loss-of-function, gain-of-function or the acquisition of a novel
function is unknown. Furthermore, although there are no mutations in MAPT that cause inherited AD, how
alterations in tau function contribute to dysfunction in neural cells and pathological aggregation of tau protein are
still incompletely understood. These issues have not been resolved, largely because the functions of the tau
protein have not been conclusively determined. While highly expressed in neurons, tau is expressed in other
CNS cell types and has been linked to cellular localizations ranging from the nucleolus to the plasma membrane.
Furthermore tau-interacting proteins display a range of cellular functions including gene regulation, membrane
transport, RNA binding and metabolism and cytoskeletal elements. Together this suggests a role for tau protein
in central nervous system cells beyond microtubule stabilization. Many studies have examined the effects of
pathological tau, but only a limited number of studies have investigated the cellular functions of wild type,
endogenous tau. Examining cellular phenotypes in the absence of tau is one approach to understand its normal
function. To date, most studies have studied tau deficiency using rodent models or transformed human cell lines
and these studies show various and sometimes conflicting results. In this study, we will use our expertise in
human induced pluripotent stem cell technology to study loss of tau function in human neural cultures and cortical
organoids. We will use CRISPR/Cas9 to disrupt the human tau reading frame, generating tau-KO cell lines. We
will then pursue both unbiased transcriptomic profiling and hypothesis-based experiments examining molecular
and physiological consequences in neurons and astrocytes deficient in tau expression. We have generated pilot
data indicating a strong up-regulation of pathways involved in neuroimmune function in tau-KO cortical cultures
compared to isogenic WT controls and we have validated our findings with shRNAs targeting MAPT. Our
proposed experiments will use hiPSC-derived neurons and astrocytes to test cell autonomous and non-cell
autonomous responses to tau deficiency. These tau deficiency phenotypes include altered granulostasis and the
accumulation of double-stranded RNA, as suggested by our preliminary studies. We will also assess
electrophysiological function of tau deficient neurons cultured with wild-type astrocytes and wild-type neurons
cultured with tau deficient astrocy...

## Key facts

- **NIH application ID:** 10823285
- **Project number:** 5R21AG079161-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Jessica Elaine Young
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $208,625
- **Award type:** 5
- **Project period:** 2023-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823285

## Citation

> US National Institutes of Health, RePORTER application 10823285, Functions of Tau protein in human neural cells (5R21AG079161-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10823285. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*