Network Disruption and Recovery Following Cell Loss in Early Stage Alzheimer’s Disease

Stacy Grunke, PhD
Baylor College of Medicine (Houston, TX)

Mentors

Joanna Jankowsky, PhD
Baylor College of Medicine (Houston, TX)
Year Awarded:
2015
Grant Duration:
July 1, 2015 to June 30, 2017
Disease:
Alzheimer's Disease
Award Amount:
$100,000
Grant Reference ID:
A2015016F
Award Type:
Postdoctoral Fellowship
Award Region:
US Southwestern
Stacy Grunke, PhD

Deconstructing Entorhinal Degeneration and Repair in Alzheimer’s Disease

Summary

Our studies will address why layer II of the entorhinal cortex, a part of the brain’s hippocampal memory system, is severely affected early in the progression of Alzheimer’s disease (AD). We will also determine whether there are mechanisms for repair of the brain circuitry that can facilitate functional recovery of memory processing once entorhinal neurons are lost.

Details

My project will explore the vulnerability of the entorhinal-dentate gyrus circuit, which is affected early in AD, and the potential for recovery following disruption of this circuit. Specifically, we will dissect the selective vulnerability of layer II of the entorhinal cortex to neural dysfunction and also explore the capacity for repair of the memory encoding circuitry following loss of entorhinal input to the dentate gyrus.

To address questions about the how the brain responds to synaptic dysfunction present at early stages of disease progression, my lab has generated a transgenic mouse in which we can selectively and reversibly inhibit the activity of entorhinal layer II neurons. Using this unique model, I have identified a novel mechanism for the early loss of entorhinal neurons in disease progression.
 
In Aim 1, we will analyze and compare the response of entorhinal cortex layers II and III to neuronal inhibition. Entorhinal cortex layer III neurons will be inactivated and the resulting cell loss will be compared to the cell loss observed after inhibiting layer II neurons. In addition, I will inject neuronal tracers into the CA1 and dentate gyrus regions of the hippocampus to further quantify the loss of synaptic connections originating from each layer of the entorhinal cortex.
 
In Aim 2, I plan to study the structural plasticity of axon terminals in the dentate gyrus following loss of entorhinal input. I will use neuronal tracing methods to measure axonal outgrowth from unaffected entorhinal neurons over the course of one day to one month following entorhinal inhibition. Similarly, I will use alternate tracing methods to measure the expansion of axonal projections to the dentate gyrus originating from other regions of the brain.
 
In Aim 3, I will examine the time course of recovery for spatial memory processing and determine whether associative or spatial memory encoding is more rapidly repaired following loss of entorhinal input to the dentate gyrus. By comparing the behavioral time course to the structural recovery in Aim 2, I will be able to correlate the timing of the structural circuit repair to the behavioral performance outcomes.
 
Future studies are being planned. I will use this research as the foundation for dissecting the impact of amyloid deposits on the sensitivity of entorhinal neurons to dysfunction, and to explore how aberrant amyloid impairs the recovery process. This line of research will help us to better understand what forms of plasticity are enlisted to cope with damage in this circuit in normal and disease states, and may, with cautious extension, allow us to guide patient expectations for recovery in the future.

About the Researcher

Stacy Grunke, PhD, is a postdoctoral fellow in the Department of Neuroscience at Baylor College of Medicine. She studied biochemistry and chemistry at Gustavus Adolphus College in St. Peter, Minn., before completing her doctoral studies in neuroscience at the University of Minnesota. Dr. Grunke’s thesis focused on generating a new model of primary brain tumors for the study of tumor invasion and progression. As a postdoctoral fellow, Dr. Grunke’s work has focused on understanding the dysfunction of the neuronal network in early stage neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease. 

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