TDP-43 Depletion as a Risk Factor for Tau Pathology in Alzheimer’s

Resham Chhabra, PhD
Johns Hopkins University (Baltimore, MD)

Mentors

Tong Li, PhD
Johns Hopkins School of Medicine (Baltimore, MD)
Philip Wong, PhD
Johns Hopkins School of Medicine (Baltimore, MD)
Year Awarded:
2017
Grant Duration:
July 1, 2017 to June 30, 2019
Disease:
Alzheimer's Disease
Award Amount:
$100,000
Grant Reference ID:
A2017102F
Award Type:
Postdoctoral Fellowship
Award Region:
US Northeastern
Resham Chhabra, PhD

I was deeply affected by the news of an elderly woman found sitting alone, unable to communicate properly, who could not recall her address. I knew there’s more to the story.

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TDP-43 Depletion as a Risk Factor Promoting Tauopathy in AD

Summary

My research aims to determine whether depletion of TAR DNA-binding protein 43 (TDP-43) in neurons contributes to pathological conversion of tau or accelerates tauopathy, a critical driver of neuron loss and cognitive decline in sporadic Alzheimer’s disease (AD). The pathological alteration and aggregation of tau protein (called tauopathy) is arguably the most important alteration in AD, as it shows the strongest association with the loss of brain cells and memory. Many studies have shown TDP-43 abnormality in 30-70% of AD cases, and that these cases show worsened memory loss. The aim of our study is to find out if TDP-43 loss plays a role in the initiation or acceleration of tauopathy in AD. Once we know what drives the changes in tau, we can halt or slow the progression of this disease. 

Details

In addition to amyloid plaques and tau tangles, which are the two pathological hallmarks that define AD, a TDP-43 abnormality has been reported to contribute to the worsening of memory in a subset of AD patients.  Studies support the idea that TDP-43 loss may indeed be a main culprit, and that loss of TDP-43’s ability to function within the nuclear compartment of nerve cells could be a risk factor influencing the alteration of the tau protein in AD brains.  It is thought that clumping of the tau protein into aggregates underlies the loss of nerve cells and ensuing memory deficits. To test whether loss of this TDP-43 protein would serve as a risk factor, we will take advantage of our newly developed AD mouse model that facilitates the clumping of normal tau protein in the presence of amyloid plaques. The results of our study will lead us to establish that TDP-43 loss is a risk factor by influencing the clumping of the tau protein. These results will point to development of drugs to halt or slow the progression of this devastating disease.

About the Researcher

Currently Dr. Chhabra is a postdoctoral research fellow in the Department of Pathology at the Johns Hopkins University School of Medicine. Her research focuses on understanding the molecular mechanisms underlying neurodegenerative diseases, with a particular interest in AD. Prior to this position, she completed her PhD in molecular medicine with a focus on neuroscience and nanomedicine at Ulm University, Germany, and an MSc degree in neuroscience, specializing in neurodegeneration, at the Institute of Psychiatry, King’s College London, England. During her master’s level training, she investigated the utility of MRI imaging in detecting early pathological changes in APP transgenic mice. Her PhD research in the field of nanoneuromedicine focused on developing novel therapeutic techniques for the delivery of bioactive substances into the CNS using nanomedical approaches. This involved testing of novel hybrid nanoparticles for targeted therapeutic delivery of proteins and/or metal ions into the CNS. In parallel, she investigated the proteins of excitatory post-synapses, specifically scaffold proteins of the Shank family. She worked on questions of how the setup and function of synapses change during development and aging, and how this ‘normal’ pattern is altered under pathological conditions. Her research covers a broad spectrum of experimental work ranging from diagnostic tools and basic science to pharmaceutical approaches. She has expertise in animal and cell model systems, transgenic mice, nanomedicine, interaction of biometals with the nervous system, neuroanatomy, cell biology and biochemistry.

Personal Story

I have always been inclined towards building a better life for the elderly. During my high school years, I was deeply affected by the news of an elderly woman found sitting alone, unable to communicate properly, who could not recall her address. The general public at that time misunderstood that situation as an extreme case of age-related cognitive decline, but being a science student, I knew there should be much more to the story. And, that’s when I came across the term Alzheimer’s disease.

The more I read about the anatomy and functioning of the brain and what happens during neurodegeneration, the more I got intrigued by the complexity of this devastating disorder. Alzheimer’s and related dementias are rapidly increasing due to an aging population, yet there are no currently available treatments that halts progression. Only by increasing our understanding of the cellular and molecular events that lead to AD’s development and/or progression can new therapeutic targets be identified. My fascination and passion for this field of research along with my parents continuing interest and support for my education led me to specialize in neurodegeneration,  and my research now focuses on the mechanisms underlying observed pathology in neurodegenerative disorders like AD, amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) and traumatic brain injury (TBI).
 
Apart from the efforts of the scientific community, another important element for advancing scientific research is the availability of funds to carry on the investigations. This would not be possible without the help and support of organizations like BrightFocus Foundation. My relationship with the foundation began during my PhD training, when I attended one of their fascinating Alzheimer’s Fast Track workshops held in Alexandria, Virginia. I am deeply thankful to all the people associated with the BrightFocus Foundation, especially the donors, for funding my research into the molecular factors that drive memory loss and cognitive decline in sporadic forms of Alzheimer’s disease that grow more common with advanced age.

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