# Mechanisms of APP ectodomain function

> **NIH NIH R35** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2024 · $426,250

## Abstract

PROJECT SUMMARY
Cell membrane proteins regulate a multitude of cellular processes that are vital for organismal health. The
extracellular domain is critical for ligand binding and signal transduction of the full-length receptor. In addition,
approximately 2% of cell surface proteins undergo ectodomain shedding to release their extracellular domain.
Ectodomain shedding may terminate the function of the full-length receptor and/or lead to the generation of either
a soluble decoy receptor or an active ligand. The Amyloid Precursor Protein (APP), a type 1 membrane protein
central to the etiology of Alzheimer’s disease, is one such cell surface protein that undergoes ectodomain
shedding to generate various soluble APP (sAPP) fragments. Despite the known effects of the APP ectodomain
on cellular and cognitive functions and the potential applications to disease, the precise molecular mechanisms
mediating the function of APP ectodomain remains largely enigmatic due to the focus of the field on the Amyloid-
β region of APP. Thus, the goal of the lab is to elucidate the normal physiological functions of the extracellular
domain of the Amyloid Precursor Protein. Our approaches are designed to address the mechanistic gaps in
knowledge by leveraging our recent discovery that sAPP functions as a ligand for the GABA type B Receptor
(GABABR) and our recent identification of Phosphoglycerate Mutase Family Member 5 (PGAM5), a mitochondrial
serine/threonine protein phosphatase, as a novel candidate interactor of the APP ectodomain. One line of
research will elucidate the cellular responses of non-neuronal cells to sAPP and GABA B Receptor modulation,
identify signaling pathways downstream of the sAPP and GABA B Receptor interaction, and determine
mechanisms involved in the positive regulation of GABA B Receptor signaling by sAPP. A second line of research
will investigate the cellular conditions and subcellular compartments in which APP and PGAM5 come into
contact, the molecular basis of the APP and PGAM5 interaction (i.e. binding affinities, critical binding domains),
and the consequences of PGAM5 on APP phosphorylation and proteolytic processing. The work in these studies
will generate fundamental knowledge of the molecular mechanisms underlying the protein-protein interactions
of the APP ectodomain and the cellular consequences of these interactions across different cell types.

## Key facts

- **NIH application ID:** 10862658
- **Project number:** 5R35GM142726-05
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** HEATHER C. RICE
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $426,250
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862658

## Citation

> US National Institutes of Health, RePORTER application 10862658, Mechanisms of APP ectodomain function (5R35GM142726-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10862658. Licensed CC0.

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