Attributions

Mitochondrial Fission at the Synapse in Alzheimer's Disease

Hwajin Kim, PhD The J. David Gladstone Institutes

Mentor

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.

Project 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.