As the sixth leading cause of death that affects over 5.2 million people, Alzheimer's disease (AD) is becoming a health crisis. To much disappointment, previous clinical trials have shown little success in finding a treatment for this devastating disease. Thus, it is critical that new and alternative molecular targets be explored. The proposed project will test the overarching hypothesis that calcineurin (CN) and connexin43 (Cx43) interactions disrupt gap junction (GJ) coupling in astrocytes during the progression of AD leading to detrimental changes in neurologic function. This project will use a multi-disciplinary approach to investigate the hypothesis using an array of AD model systems, including human hippocampal specimens, APP/PS1 transgenic mice, and rat primary astrocyte cultures. In addition to the excellent model systems, this project will use a variety of cutting-edge techniques, including fluorescence resonance energy transfer (FRET), adeno-associated virus (AAV) - mediated gene delivery, and slice electrophysiology. The overarching hypothesis will be examined through three independent specific aims which are as follows: to test the hypothesis that CN interacts with Cx43 during the progression of AD using techniques such as FRET and co-immunoprecipitations (Co-IPs); to test the hypothesis that beta amyloid (A-beta) disrupts gap junction (GJ) coupling in a CN-dependent manner using techniques such as dye coupling and Western blot; to test the hypothesis that CN/Cx43 interactions disrupt GJ coupling and neurologic function in a mouse model of AD using cognitive measures such as the active avoidance paradigm and techniques such as dye coupling, Western blot, and slice electrophysiology. This project not only provides superior training in neuroscience research, but also will provide extremely valuable information into a potential new therapeutic target for AD.

Public Health Relevance

As the sixth leading cause of death that affects over 5.2 million people in the United States; Alzheimer's disease (AD) is becoming an impending health crisis. To much disappointment; previous clinical trials have shown little success in finding a treatment for this devastating disease. Thus; it is critical that new and alternative molecular targets be explored; which is the goal of the proposed research.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AG047762-03
Application #
9208728
Study Section
Special Emphasis Panel (ZRG1-F05-R (20)L)
Program Officer
Petanceska, Suzana
Project Start
2015-02-01
Project End
2018-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
$30,876
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Furman, Jennifer L; Sompol, Pradoldej; Kraner, Susan D et al. (2016) Blockade of Astrocytic Calcineurin/NFAT Signaling Helps to Normalize Hippocampal Synaptic Function and Plasticity in a Rat Model of Traumatic Brain Injury. J Neurosci 36:1502-15
Pleiss, Melanie M; Sompol, Pradoldej; Kraner, Susan D et al. (2016) Calcineurin proteolysis in astrocytes: Implications for impaired synaptic function. Biochim Biophys Acta 1862:1521-32