# A novel systems analysis of a synaptic gene network

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $250,000

## Abstract

With the increase of the elderly population in recent decades, Alzheimer's disease (AD) is
quickly becoming a public health concern. The disease causes loss of memory, confusion and
affects decision-making. With the few exceptions of familial AD cases linked to APP and ApoE4
as a risk factor, most AD cases have unknown ethiology. Therefore, a major effort has been
directed to identify genes associated with AD with the goal of developing better diagnostic tools
and new therapies for the disease. The majority of the strategies to identify AD markers, targets,
predictors and risk factors still rely on Genome Wide Association Studies (GWAS), which are
known for high costs and a high rate of false positives. In contrast, our study starts with a
synaptic network of proteins required for decision-making in Drosophila, which is conserved in
flies and in humans. This synaptic network is composed of genes that have DNA binding sites of
DATI, a conserved transcription factor that allows female flies to either accept or reject males.
Remarkably, 88% of the genes in this network are present in the human genome and 100% of
these human genes also contain DATI binding sites, indicating that this is a very deeply
conserved gene network likely to be of significance to understand higher cognitive functions.
Consistent with this view, 10% of the proteins of the network interact with APP and 13% of the
genes listed in AGORA as candidates for AD are part of this network. Together, these data
make a strong case that this network is significant for understanding AD. In addition to
identifying these genes, this project seeks to understand how these genes lead to the
emergence of cognitive functions. To begin addressing this question, we have been using a
series of tools to analyze multidimensional data in 3D space in intact brains. These tools allow
us to analyze in fluorescently labeled neurons how the knockdown of a gene of the network
modifies the levels and localization of other genes of the network using Geographic Information
Systems. This administrative supplement request will partially support the acquisition of a new
instrument, the Zeiss LSM900 confocal microscope with Airyscan 2. To a significant extent, the
throughput of these analyses depends on the scanning speed of the confocal microscope, the
resolution required, the sensitivity and automation in the process. We expect that the acquisition
of this new compact confocal system will allow us to increase the throughput and resolution of
our analyses, ultimately increasing the impact of our study.

## Key facts

- **NIH application ID:** 10410170
- **Project number:** 3R01AG061390-04S1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Rui Sousa-Neves
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $250,000
- **Award type:** 3
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10410170

## Citation

> US National Institutes of Health, RePORTER application 10410170, A novel systems analysis of a synaptic gene network (3R01AG061390-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10410170. Licensed CC0.

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