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 (A?) peptides that accumulate in AD, and clinical trials have focused on reducing A? levels in patients. Unfortunately, these trials have not substantially improved patient outcomes, and the mechanisms of A? 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 A? can directly bind APP, suggesting that A? 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 Go?. Studies in cell culture have shown that APP can bind and activate Go? via a conserved cytoplasmic motif, while chronic stimulation of APP-Go? signaling in transfected cells provokes Ca2+ overload and apoptosis. Mutated forms of APP linked with AD can also hyperactivate Go?, 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-Go? signaling remained controversial. Using insect models as convenient in vivo assays, we demonstrated that APP family proteins regulate Go?-dependent neuronal guidance in the developing nervous system. Likewise, we showed that APP- Go? signaling controls the motile behavior of cultured murine hippocampal neurons. Based on these studies, we have now discovered that A? oligomers may cause aberrant APP-Go? 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 A? disrupt the APP-Go? signaling pathway.
In Aim 1, will first define the normal role of APP-Go? 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-Go? signaling regulates synaptic formation and function.
In Aim 2, we will test how neurotoxic forms of A? affect aspects of synaptogenesis and function that are regulated by APP-Go? signaling, complemented by experiments using APP knockout mice and a transgenic line that overexpresses human A?.
In Aim 3, we will use human brain samples to evaluate how APP-Go? 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-Go? pathway is misregulated. Public Heath Relevance: Defining the mechanisms by which misregulated APP-Go? signaling affects neuronal viability could lead to the development of new therapeutic targets for diagnosing and treating AD, particularly in its initial stages.

Public Health Relevance

This exploratory proposal will investigate how altered interactions between the Amyloid Precursor Protein (APP) and the signaling protein Go? provoke neurodegeneration in Alzheimer's disease (AD). Using mouse hippocampal neurons, we will determine the normal function of APP-Go? signaling, and then test how neurotoxic amyloid (linked with AD) disrupts this pathway. In addition, we will explore how APP-Go? interactions are altered in AD patients, with the goal of discovering a new strategy for treating AD.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Corriveau, Roderick A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Oregon Health and Science University
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code