# A novel systems analysis a synaptic gene network

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $402,292

## Abstract

ABSTRACT
Alzheimer's disease (AD) is one of the most common diseases that afflict the elder population.
The disease causes loss of memory, confusion and affects decision-making. The effort made in
past decades led to the identification of some significant genes associated to AD. For example,
5% of the AD cases are associated to the APP gene, 20-50% are associated to ApoE4 and the
remaining receive designations like ApoE4 non-carriers and sporadic AD. However, ApoE4 is
considered to be a risk factor. Thus, most cases of AD still have an unclear etiology. This
scenario began to change with the discovery that βA regulates the activity of the nAChRα7
nicotinic receptor by potentiating the receptor activity at low concentrations and inhibiting it at
high concentrations. Together these and other observations make a strong case that AD might
be a disease with an origination in synaptic dysfunction. However, that possibility poses a
problem because synapses possess extremely complex networks and we still have a limited
understanding of their complex regulation. Also, these networks are different in different
neurons and not all of them are dedicated to cognitive function, which makes it extremely
difficult to select the correct network and understand its organization and function. To overcome
these hurdles, here we propose a systems approach to identify within a conserved synaptic
network required for cognitive functions, those components effectively required for cognitive
functions. Our preliminary data provide strong evidence that several genes we identified as part
of a cholinergic synaptic network required in decision-making are associated either APP or βA.
To understand how the mis-regulation of these genes leads to synaptic dysfunction we propose
a series of experiments using Bubble Maps, a powerful platform developed by our group. This
platform allows for analyzing complex 3D data with single cell resolution and geospatial
referencing across multiple dimensions such as time, spatial location, levels of gene and protein
expression, cell volumes, chromatin condensation, among others. Bubble Maps provides the
first implementation of Geographical Information Systems (GIS) to retrieve fine resolution
information of a complex cellular/molecular network. GIS is a robust system used for data
management, map pattern analyses, spatial statistics, spatial location using attribute-based
queries, and modeling spatial relationships. We expect that Aim1 will lead to the discover novel
components of this synaptic network effectively required for decision-making, expand the
number of second and third order interactors, and provide a broader view of the network and its
edges; Aim 2 will validate the biological functions of these genes, establish regulatory
relationships between them and define how these relationships contribute to proper connectivity
and performance of these neurons; Aim 3 will test if disturbances in this network leads to
synaptic dysfunction and ...

## Key facts

- **NIH application ID:** 9934086
- **Project number:** 5R01AG061390-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Rui Sousa-Neves
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,292
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934086

## Citation

> US National Institutes of Health, RePORTER application 9934086, A novel systems analysis a synaptic gene network (5R01AG061390-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9934086. Licensed CC0.

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