# Functional Genomic Dissection of Alzheimer's Disease in Humans and Drosophila Models

> **NIH NIH U01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $401,250

## Abstract

ABSTRACT
Alzheimer’s disease (AD) susceptibility loci are enriched for genes implicated in the endolysosomal pathway
(ELP) and lipid homeostasis (LH), and these biological processes are highly interdependent. The AD Sequencing
Project (ADSP) Functional Genomics Consortium (FunGen) selected the ELP/LH pathways as high-priorities for
cross-cutting, collaborative investigations, culminating in 3 applications for supplemental funding. Together,
investigators from 4 distinct U01 FunGen projects will probe ELP/LH mechanisms of AD risk using a tiered
strategy integrating experiments in Drosophila with both 2D and 3D human iPSC cultures. We recently showed
that APOE and several other AD susceptibility / ELP genes (PICALM, CD2AP, AP2A2) participate in a common
pathway involving the formation of lipid droplets (LD) within glia. Glial LD formation involves two related
mechanisms. The first is a non-cell autonomous neuroprotective pathway where LD form within glia in response
to elevated reactive oxygen species (ROS) in neurons. These glial LDs are composed of toxic, peroxidated lipids
(LPO) produced by “stressed” neurons and these LPO are catabolized within the glia, effectively removing the
LPO from the brain and protecting both cell types from ROS-induced damage. The second mechanism involving
glial LD formation is a cell autonomous mechanism whereby APOE4 or loss of PICALM directly drives glial LD
formation in response to stress. This causes high LD load and may be important in later-stage AD pathologic
changes. We hypothesize that many other AD risk genes may participate in either one or both of these pathways,
having divergent impact on AD risk, glial LD load, and neuronal oxidative stress/injury, depending on the disease
stage(s) and cell type(s) affected. Here, we propose systematic functional dissection of 50 AD candidate genes,
using well-established Drosophila protocols to establish cell-type specific requirements for glial LD formation,
potential interactions with ROS, and resulting neurodegeneration. Gene selection will be closely coordinated with
FunGen collaborators and informed by complementary, high-throughput screens considering more than 1000
genes in iPSC and Drosophila models, revealing interactions with amyloid-beta / tau-induced neurodegeneration
and requirements for ELP/LH. Overall, our integrated FunGen supplemental research program will promote
highly synergistic studies not otherwise possible within the scope of individual projects, revealing ELP/LH
mechanisms of AD risk, identifying promising therapeutic targets, and culminating in a joint consortium
manuscript.

## Key facts

- **NIH application ID:** 11124474
- **Project number:** 3U01AG072439-04S1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** HUGO J BELLEN
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $401,250
- **Award type:** 3
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11124474

## Citation

> US National Institutes of Health, RePORTER application 11124474, Functional Genomic Dissection of Alzheimer's Disease in Humans and Drosophila Models (3U01AG072439-04S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/11124474. Licensed CC0.

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