# Functional assessment of 1,500 human genes against coexistent Abeta and tau pathology in vivo

> **NIH NIH R21** · UNIVERSITY OF FLORIDA · 2021 · $190,625

## Abstract

Alzheimer’s disease (AD) is an incurable neurodegenerative brain disorder that causes progressive memory loss
and cognitive decline, and is the most common form of dementia. It is characterized by the coexistence of
extracellular amyloid plaques, mainly formed by the amyloid beta-42 (Abeta) peptide, and intracellular
neurofibrillary tangles containing aggregates of abnormal tau. Abeta and tau were considered as disconnected
culprits for many years, but in view of recent studies, it is clear that they are intimately related and possess
synergistic activities. Sadly, very little is known about how Abeta and tau interactions trigger AD pathogenesis,
which significantly hinders the development of effective treatments. To address this, we created a new fly model
of AD that genetically produces both human Abeta and tau resulting in synergistic pathology. These flies display
extracellular deposits of Abeta, intracellular aggregation of pathological tau, and progressive neurodegeneration.
Our preliminary data show that the robust and consistent pathology of these flies represents an ideal platform
for gene discovery initiatives. Therefore, we propose to use these flies to functionally assess the first large
collection of transgenic flies expressing human genes. This collection includes many AD risk genes, identified
by Genome Wide Association Studies (GWAS) or Next Generation Sequencing (NGS), whose functional role in
the disease is poorly understood. Thus, we will cross our Abeta+tau flies with 1,500 strains engineered to
specifically activate human HA-tagged cDNAs with similar expression levels. We will first test them in the fly eye,
which provides a useful and easy-to-score phenotype to assess the effect of co-expressing every human gene
with Abeta and tau (Aim 1). Then, we will validate the stronger suppressors for their ability to alter the course of
neuropathology in the fly brain using cellular, histological and behavioral approaches (Aim 2). We strongly
believe that the screen of this new and distinctive library will lead to a rapid identification of relevant hits mediating
pathological interactions between Abeta and tau, and will unveil a set of key human targets for immediate
translational studies. Therefore, this work may contribute significantly to the goals of the National Plan to Address
Alzheimer’s Disease.

## Key facts

- **NIH application ID:** 10224098
- **Project number:** 5R21AG069050-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Diego E Rincon-Limas
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $190,625
- **Award type:** 5
- **Project period:** 2020-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224098

## Citation

> US National Institutes of Health, RePORTER application 10224098, Functional assessment of 1,500 human genes against coexistent Abeta and tau pathology in vivo (5R21AG069050-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10224098. Licensed CC0.

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