# Normal and abnormal control of APP signaling

> **NIH NIH R21** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $192,500

## Abstract

The overall goal of this exploratory project is to investigate how the misregulation of normal signaling by the
Amyloid Precursor Protein (APP) might contribute to Alzheimer's disease (AD). APP is best known as the
source of beta amyloid (Aβ) peptides that accumulate in AD, and clinical trials have focused on reducing Aβ
levels in patients. Unfortunately, these trials have not substantially improved patient outcomes, and the
mechanisms of Aβ toxicity are still under debate. At the same time, growing evidence has shown APP itself
may serve important functions in the brain, including synaptogenesis, remodeling, and regrowth responses
following injury. In addition, neurotoxic forms of Aβ can directly bind APP, suggesting that Aβ might also
provoke neurodegeneration by perturbing the normal functions of APP. Although APP may interact with a
variety of signaling molecules, compelling work has now shown that it can function as an atypical G protein-
coupled receptor, specifically regulating the heterotrimeric G protein Goα. Studies in cell culture have shown
that APP can bind and activate Goα via a conserved cytoplasmic motif, while chronic stimulation of APP-Goα
signaling in transfected cells provokes Ca2+ overload and apoptosis. Mutated forms of APP linked with AD can
also hyperactivate Goα, while the severity of AD symptoms in human patients corresponds with a general
elevation in G protein activity. Until recently, however, authentic roles for APP-Goα signaling remained
controversial. Using insect models as convenient in vivo assays, we demonstrated that APP family proteins
regulate Goα-dependent neuronal guidance in the developing nervous system. Likewise, we showed that APP-
Goα signaling controls the motile behavior of cultured murine hippocampal neurons. Based on these studies,
we have now discovered that Aβ oligomers may cause aberrant APP-Goα signaling in cultured neurons,
resulting in the loss of dendritic complexity and synaptic function. Accordingly, we will explicitly test the
hypothesis that neurotoxic forms of Aβ disrupt the APP-Goα signaling pathway. In Aim 1, will first define the
normal role of APP-Goα signaling in cultured mouse hippocampal neurons. We will use a combination of
biochemical assays, gene knockdown and re-expression methods, and advanced imaging strategies to define
how APP-Goα signaling regulates synaptic formation and function. In Aim 2, we will test how neurotoxic forms
of Aβ affect aspects of synaptogenesis and function that are regulated by APP-Goα signaling, complemented
by experiments using APP knockout mice and a transgenic line that overexpresses human Aβ. In Aim 3, we
will use human brain samples to evaluate how APP-Goα interactions change over the course of AD, compared
to healthy age-matched controls. Future studies will focus on identifying downstream effectors that provoke
neurodegenerative responses when the APP-Goα pathway is misregulated. Public Heath Relevance:
Defining the mechanisms by which misregu...

## Key facts

- **NIH application ID:** 9840511
- **Project number:** 5R21NS109884-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** PHILIP F COPENHAVER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $192,500
- **Award type:** 5
- **Project period:** 2019-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840511

## Citation

> US National Institutes of Health, RePORTER application 9840511, Normal and abnormal control of APP signaling (5R21NS109884-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9840511. Licensed CC0.

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