Implication of a Mitochondrial Protein, ECSIT, in the Oxidative Stress Leading to Alzheimer’s Disease

Alice Lepelley, PhD Columbia University Medical Center


Sankar Ghosh, PhD Columbia University Medical Center


Alzheimer’s disease is the world’s most common cause of dementia, and oxidative stress has emerged as a key feature and possible cause of the disease. It appears early and can accelerate progression of the disease. However, only a few treatments directed towards preventing oxidative stress have produced positive results. With this project, we will study a promising novel mechanism causing oxidative stress in hopes of stimulating ideas for more efficient therapeutics.

Project Details

Evidence is accumulating that oxidative stress in the brain is the key causative factor of Alzheimer’s disease (AD). However, attempts to curb it have shown little efficacy. In this project, we are studying the role of a promising novel mechanism in the establishment of oxidative stress leading to AD. Our laboratory has already implicated this pathway and, in particular, a candidate gene in oxidative stress regulation. Moreover, studies by others have shown that this candidate gene might interact with key factors leading to the development of the disease.

We are first investigating the relevance of this mechanism in important cells of the brain, neurons and microglia. Indeed, neuronal death and microglial cell activation are key elements leading to AD and the regulation of oxidative stress is involved in these processes. We will use cell culture experiments to study the role of our candidate gene in the induction of oxidative stress in these cells.

A hallmark of AD is amyloid plaque deposition and microglial cells are able to prevent this accumulation in normal conditions through a process called phagocytosis. In AD, phagocytosis is altered and microglial cells are hyperactivated. We are studying the contribution of the novel pathway we described in amyloid plaque deposition and the subsequent response of microglial cells, which might contribute to the disease.

Finally, we plan to evaluate the contribution of our candidate gene to the onset and development of AD in a mouse model. To do so, we will combine lines of mice genetically engineered to develop AD with lines of mice missing our candidate gene in the brains. We will monitor mice behavior, memory function and alterations in the brain to understand whether our candidate pathway contributes to the disease.

Our laboratory is pioneering research about this novel pathway involved in oxidative stress regulation. Thus we are the only laboratory having all the tools to study its implication in AD. In particular, we have developed a unique genetic tool to investigate its role in a model of the disease. We also are also poised to benefit from the strong expertise of several laboratories working on AD research on our medical center campus. We are confident about the relevance of this project, especially because studies suggested that our candidate gene lies in a network of genes already implicated in AD development.

The results of this study will confirm and give more insight into the role of oxidative stress in AD onset and pathogenesis. In addition, they will help identify promising targets in the oxidative stress pathway, helping us to design novel and more efficient therapeutics in the prevention and treatment of Alzheimer’s disease.