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Alzheimer's Disease Research
Current Award

Dr. Jian Li

Jian Li, PhD

Northwestern University
Evanston, IL

Title: Stress Response Networks in Organismal Proteostasis
Non-Technical Title: Protection against Alzheimer's Disease-Associated Toxicity by Integrated Stress Response Pathways

Mentor:
Richard I. Morimoto, PhD
Northwestern University

Duration: July 1, 2014 - June 30, 2016
Award Type: Research Fellowship
Award Amount: $120,000

Summary:

Patients with Alzheimer's disease have aggregations of abnormally folded beta amyloid proteins in their brain that interfere with cellular functions and eventually lead to degeneration of neurons. It has been suggested that stress response factors may protect against this protein toxicity associated with Alzheimer's disease. This protection could occur both in the beta amyloid-expressed tissue and in the neighboring tissues. Here we set out to characterize the protective mechanisms mediated by stress response pathways, especially how neurons sense the toxic aggregation of beta amyloid and how they communicate with neighboring tissues to provide organisms with some protection.

Details:

The goal of the project is to elucidate the molecular mechanisms by which protective stress responses prevent the toxicity of aggregation-prone beta amyloid (Aβ) protein. Alzheimer's disease patients are featured with aggregation of abnormally folded beta amyloid proteins in the brain that interfere with the cellular functions of neurons and eventually lead to their degeneration. It has been suggested that stress response factors may protect against the proteotoxicity associated with Alzheimer's disease. However the molecular mechanisms are still poorly understood.

We hypothesize that different stress response pathways are integrated in a coordinated network and enable the protection against Aβ proteotoxicity that occurs both in the Aβ expressed tissue and the neighboring tissues. Here we set out to use the C. elegans models of Alzheimer's disease to characterize the protective stress response network, focusing on how neurons sense the toxic Aβ aggregation and how they communicate with neighboring tissues to achieve an organismal protection.

The first aim of the study is to identify the molecular functions of evolutionarily conserved transcription factors involved in responses to different cellular stresses, such as heat stress, oxidative stress and unfolded protein stress in the context of Aβ proteotoxicity. We will examine both the Aβ expressed neurons and the neighboring tissues to dissect the cell autonomous and non-autonomous responses. We expect Aβ toxicity does not only trigger stress responses in neurons, but also causes imbalance of protein homeostasis, and thus induces stress responses in neighboring tissues as well. On the other hand, the responses in distal tissues may provide positive feedback and enhance the protective stress responses in neurons. This trans-cellular signaling could provide a way of integrating different stress response pathways that have tissue specificity and end up with robust organismal protection. The second aim of the study is to examine the impact of aging and chronic proteotoxicity on stress responses. To test the hypotheses that aging and/or chronic proteotoxicity impair the protective responses, we will characterize the integrated stress response network in neurons and neighboring tissues in animals of different ages and with different lengths of exposure to Aβ aggregates. These studies will elucidate the interactions of aging, stress response, and gain-of-function impacts of Aβ aggregation, and also shed light on the potentials for re-engineering the stress response pathways for extended protection during aging.

Investigator Biography:

I am currently a postdoctoral fellow in the laboratory of Richard Morimoto, PhD, at Northwestern University. I completed my PhD in biochemistry and molecular biology at Pennsylvania State University, working with David Gilmour, PhD, where I investigated the mechanisms by which sequence-specific DNA binding factors control promoter-proximal pausing of RNA polymerase II, an important regulatory step of transcription in metazoans. My current work utilizes the C. elegans models of Alzheimer’s disease to study the protective stress responses to beta amyloid toxicity at the organismal level.