# Developing new conditional models to study tauopathy, amyloidosis, and their interaction

> **NIH NIH R33** · UNIVERSITY OF FLORIDA · 2021 · $1,817,356

## Abstract

The MPIs for this proposal independently co-developed and thoroughly characterized some of the most
commonly used mouse models for research on Alzheimer’s disease and related disorders (ADRD); however, all
existing tau and/or amyloid mouse models still have shortcomings which limit their utility and the questions that
they can be used to answer. For example, the rTg4510 model which expresses human P301L tau through a
doxycline-repressible system is one of the gold standard models in the field; however, rTg4510 is limited, in part,
by its dependence on two unlinked transgenes, the early onset of tauopathy and cognitive dysfunction, and the
leakiness of the tau expression. The overall goal of this proposal is to develop new models for the
Alzheimer’s Disease field that overcome the shortcomings of existing models, ultimately providing an
innovative platform in which the sequential nature of amyloidosis and tauopathy and the molecular
pathways underlying their interaction can be examined in a streamlined, cost-effective manner. Under
Aim 1, we propose to generate a model in which the CamKII-tetracycline transactivator transgene and the tau
responder transgene (either WT or P301L) required for the conditional expression of tau will be co-injected and
thus co-integrated into the murine genome which can subsequently transmit as a single allele. We will strive to
develop a P301L tau/tTA model that will develop pre-tangle pathology at 12-15 months and tangles at 18 months
of age. This new model will subsequently be fully characterized biochemically, pathologically, cognitively and
structurally using MRI. Once established, these novel, conditional tau transgenics will provide a less expensive,
more accessible model that develops tauopathy in mid to late life; enabling both studies aimed at accelerating
and at slowing/abrogating the tauopathy. We also anticipate that this model, like the JNPL3 and rTg4510 tau
models, will develop neuroinflammation and secondary TDP-43 proteinopathy. Under Aim 2, we propose to
create a new conditional APP transgenic model through co-injection/co-integration using the cumate-repressible
system to control APPswe/ind expression. No mouse model utilizes the cumate-repressible system in the brain
and simply having the APP transgene under this alternatively conditional system positions this model for use in
studies to identify interactions between APP and tau, ?-synuclein or other potential interactors. Finally, under
Aim 3, we will crossbreed the new, single allele, tetracycline-repressible tau model with the single allele, cumate-
repressible APP to allow the dissection of the interaction between tau (tauopathy) and APP (amyloidosis) in a
sequential and systematic fashion. This innovative model, requiring a cost-effective, single breeding, permits
independent control of both the tau and APP transgenes and will position the field to fill critical gaps in knowledge
that no existing animal model in the AD arena currently allows.

## Key facts

- **NIH application ID:** 10458822
- **Project number:** 4R33NS115178-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Jose Francisco Abisambra
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,817,356
- **Award type:** 4N
- **Project period:** 2019-09-17 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10458822

## Citation

> US National Institutes of Health, RePORTER application 10458822, Developing new conditional models to study tauopathy, amyloidosis, and their interaction (4R33NS115178-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10458822. Licensed CC0.

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