# Investigating Mechanisms of Neurodegeneration in Transgenic Mouse Models of Tauopathies

> **NIH NIH F30** · UNIVERSITY OF FLORIDA · 2021 · $42,366

## Abstract

Project Summary/Abstract
 Alzheimer’s disease (AD) is the most common neurodegenerative disease that affects over 25 million people
worldwide. In AD, hyperphosphorylated tau inclusions like neurofibrillary tangles are one of the earliest changes
and can predict clinical severity. As tau inclusions increase, cognitive decline and memory loss worsen over time.
Since familial and sporadic AD share the same pathology and clinical symptoms, transgenic mice that express
human tau can effectively model AD. However, many existing tau mouse models do not develop both cognitive
deficits and robust pathology in the cortex and hippocampus, which are the primary regions of neurodegeneration
in AD. In the field, there is a compelling need to develop an effective animal model of tauopathies for mechanistic
and therapeutic studies. A good model of tauopathies must meet at least four criteria: 1) develops progressive
phosphorylated tau inclusions; 2) affects the primary brain regions of cortex and hippocampus like in AD patients;
3) causes cognitive deficits; and 4) is reproducible with stable germline transmission.
 To meet this demand, my main translational research goal is to develop a robust animal model for 1. studying
disease mechanisms of tau aggregation and hyperphosphorylation and for 2. rapid screening of drugs and
therapies. Given that mice have much shorter lifespans, expression of a single disease-causing mutation may
not be sufficient to induce a robust disease phenotype. In the field of neurodegeneration, multiple pathogenic
mutations are commonly used to accelerate disease phenotypes in transgenic mice. For example, 3XTg-AD and
5XFAD mouse models use three and five different mutations of multiple genes respectively. As a result, I chose
to enhance tau neurotoxicity by combining two disease-causing mutations (P301S/S320F) in the same gene.
For this research proposal, my lab and I used pronuclear integration to generate novel transgenic mice for stable
germline expression of the tau mutations P301S/S320F. With this unprecedent mouse model, I will determine
the role of tau hyperphosphorylation in promoting tau aggregation, cognitive deficits and brain atrophy in Specific
Aims 1 and 2. In Specific Aim 3, I will use this novel mouse model to screen phospho-tau immunotherapies.
Upon completion of this study, I will fulfill my fellowship training goals of studying disease mechanisms of tau-
induced neurodegeneration and developing novel immunotherapies for the treatment of AD.

## Key facts

- **NIH application ID:** 10140917
- **Project number:** 1F30AG067673-01A1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Yuxing Xia
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $42,366
- **Award type:** 1
- **Project period:** 2021-03-08 → 2025-03-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140917

## Citation

> US National Institutes of Health, RePORTER application 10140917, Investigating Mechanisms of Neurodegeneration in Transgenic Mouse Models of Tauopathies (1F30AG067673-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10140917. Licensed CC0.

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