Reversal of Mitochondrial Fragmentation as Therapeutic Target for AD

Hwajin Kim, PhD
The J. David Gladstone Institutes (San Francisco, CA, United States)
Year Awarded:
2012
Grant Duration:
July 1, 2012 to June 30, 2014
Disease:
Alzheimer's
Award Amount:
$100,000
Grant Reference ID:
A2012629
Award Type:
Postdoctoral Fellowship
Award Region:
US Southwestern

Mitochondrial Fission at the Synapse in Alzheimer's Disease

Mentors

Ken Nakamura, M.D., Ph.D. (Primary Mentor), Lennart Mucke, M.D., (Co-Mentor)
 Gladstone Institutes

Summary

Mitochondria are vital organelles that generate energy. The fragmentation of mitochondria appears to play an important role in the pathogenesis of Alzheimer's disease (AD). In this project, Dr. Hwajin Kim is studying the mechanisms by which mitochondrial fission may contribute to AD and is testing whether reversal of mitochondrial fission may be an effective therapeutic strategy for preventing AD progression.

Details

Alzheimer's disease (AD) is the most common dementia. Although the mechanisms that contribute to the development of AD are unknown, mitochondrial dynamics, specifically, the balance between fusion and fission, play critical roles. In AD, amyloid beta produces an excessive increase in mitochondrial fission, causing mitochondria to split into multiple, smaller organelles.  This occurrence is dependent on the mitochondrial fission protein, Drp1. Mutations of Drp1 result in changes in mitochondrial dynamics and distribution leading to dysfunction. Dr. Hwajin Kim hypothesizes that reversing a normal balance will rescue mitochondrial dysfunction and neural death in AD models.

These studies are testing this hypothesis in three specific aims. In Aim 1, Kim and colleagues will define the normal role of mitochondrial fission at the synapse, where neurons connect to one another. They will use mice with a targeted genetic deletion of Drp1 in hippocampal neurons to visualize mitochondria using a combination of virally delivered genetic information and electron microscopy.  The second aim will determine if decreasing mitochondrial fission blocks the effect of amyloid beta on mitochondria. They will further examine if loss of Drp1 can restore normal function by blockage of excessive mitochondrial fission. The final goal of the work will determine if restoring normal mitochondrial fission blocks neurodegeneration in AD.

This study is applying newly developed methods to assess bioenergetic function of mitochondria in individual neurons in vivo. These results will be useful for developing a clinically feasible suppression of mitochondrial fission and Drp1 in AD.

About the Researcher

Dr. Hwajin Kim is a postdoctoral fellow of Neurological Diseases at the Gladstone Institutes at San Francisco. She previously held positions at Columbia University Medical Center and completed her doctoral studies at Northwestern University at Chicago. Kim's research focuses on bringing a cell and molecular biology perspective to the study of Alzheimer's disease. She is involved in developing new methods of measuring mitochondrial energy expenditure during synaptic transmission in normal and diseased conditions and finding therapeutic intervention by manipulating mitochondrial fission and fusion dynamics.