# Functional Dissection of Alzheimer's Disease Networks in Drosophila: from Association to   Causal Modulators of Age-Dependent Neurodegeration

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $858,120

## Abstract

Analyses of high-throughput human data, including gene expression profiles of human brains, constitute a
powerful strategy for nominating biological networks associated with Alzheimer’s disease (AD) pathophysiology
as potential therapeutic targets. The Accelerating Medicines Partnership-Alzheimer’s Disease (AMP-AD)
Target Discovery Project has defined consensus, AD-associated molecular networks based on joint analyses
of transcriptomic profiles in ~2,000 human brain autopsy samples. The critical next step is to rigorously test
computational predictions in experimental animal models to (i) unambiguously link promising networks to
specific AD triggers (i.e. Amyloid-ß, Tau, and/or aging), (ii) confirm the network architecture, (iii) validate
implicated molecular pathways in the nervous system context, and (iv) discover which molecular changes are
truly causal, including distinguishing between amplifiers of pathogenesis versus protective, compensatory
responses. We have developed a cross-species strategy for functional dissection of emerging AD molecular
networks using high-throughput assays in the nervous system of transgenic Drosophila expressing human
wild-type human Tau or the Amyloid-ß peptide. When applied to candidates from AD-associated networks,
these rapid and complementary in vivo assays enable identification of those genes and pathways that are likely
causal modifiers of Tau- and/or Aß-induced neuronal dysfunction, including both drivers of pathogenesis and
compensatory responses. The overall goal of this proposal is to deploy our cross-species strategy to
accelerate the discovery, refinement, and functional dissection of AD molecular networks derived from human
brain transcriptomes and proteomes. First (AIM 1), transcriptomic and proteomic profiling in Drosophila AD
models will be coupled with comprehensive screening of conserved network candidates in order to identify
those genes causally linked to neurodegeneration and differentiate in vivo interactions with Tau-, Aß-, or other
age-dependent mechanisms. The proposed screen will deploy robotic instrumentation for high-throughput,
quantitative analyses of Drosophila motor impairment due to neuronal dysfunction. Second (AIM 2), using
systems biology approaches, gene expression and functional data from Drosophila will be integrated with the
human AD networks. The resulting multi-scale atlas of AD molecular systems will pinpoint causal networks and
key gene/protein drivers with the greatest potential to alter neurodegeneration upon perturbation. Next (AIM 3),
we will experimentally confirm the network architecture for the most promising modules highlighting key drivers
with roles as AD amplifying/protective factors. Lastly (AIM 4), all project results will be made publicly available
via the AMP-AD Knowledge Portal. IMPACT: Our integrative, cross-species discovery strategy will
comprehensively probe AD molecular networks with powerful, in vivo functional assays to reveal age-
dependent drive...

## Key facts

- **NIH application ID:** 10174654
- **Project number:** 5R01AG057339-05
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Juan Botas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $858,120
- **Award type:** 5
- **Project period:** 2017-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10174654

## Citation

> US National Institutes of Health, RePORTER application 10174654, Functional Dissection of Alzheimer's Disease Networks in Drosophila: from Association to   Causal Modulators of Age-Dependent Neurodegeration (5R01AG057339-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10174654. Licensed CC0.

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