Using Brain Slices to Understand and Target Tau in Alzheimer's Disease

Cara Croft, PhD
University of Florida (Gainesville, FL)

Mentors

Todd Eliot Golde, MD, PhD
University of Florida (Gainesville, FL)

Collaborators

Nicholas Seyfried, PhD
Emory School of Medicine (Atlanta, GA)
Year Awarded:
2018
Grant Duration:
July 1, 2018 to June 30, 2020
Disease:
Alzheimer's Disease
Award Amount:
$150,000
Grant Reference ID:
A2018149F
Award Type:
Postdoctoral Fellowship
Award Region:
US Southeastern

Understanding and Targeting Tau-Induced Neurodegeneration

Summary

Tau is one of the two major proteins (along with beta amyloid) that changes and then builds up in the brain in Alzheimer’s disease (AD) and how it is linked to brain cell death is still unclear. I keep small sections of mouse brain tissue alive in dishes and use viruses to make them develop the buildup of tau that is seen in AD patients. First, I will look at changes in these mouse brain tissues that have tau buildup, and those that do not, to see why or if brain cells die. I then hope to treat these brain tissues to either prevent or treat the buildup of tau in order to understand if we are able to treat humans with AD in a similar way.

Details

Tau (along with beta amyloid) is one of the two major proteins that changes and then builds up in the brain in Alzheimer’s disease (AD). How tau causes brain cells to die is still unclear. Until now, we have been limited by the models available to efficiently and rapidly develop new treatments targeted against tau and the associated failure of brain cells to perform their normal functions.  

We have developed new study methods using mouse brain slices, which can be kept alive for several months at a time, and viruses to express genes linked to the buildup of tau in AD in these slices. The buildup of tau in the brain slices is similar to what is seen in human AD. Using these methods, I will first look at changes in these mouse brain slices that have tau buildup, and those that do not, to see how brain cells develop functional problems and die. I will use genetic, biochemical, and imaging approaches to answer this question.

I will then secondly confirm whether these brain slices that accumulate tau are suitable for screening for new treatments against the buildup of tau and the damage it causes. I will do this by using both genetic targets and small molecule compounds to see if the course of disease can be altered.

These experiments are innovative because the system we are using will accelerate research in the field by answering fundamental questions about how tau results in neurodegeneration. The proposed experiments would have been a heroic undertaking in the previous models available, but with our novel methods, the research planned is sustainable in the timescale.

 
This planned research should shed light on how tau is linked to the death of brain cells and the disruption of their normal function. This could potentially lead to new targets to prevent or treat this aspect of AD. In addition, the experiments planned will determine whether our system can be used to screen efficiently and effectively for new treatments accelerating the current drug development pipeline. Overall, this is exciting work which should advance our understanding of AD.

About the Researcher

I completed an undergraduate master’s degree in neuroscience at the University of Manchester, UK, before embarking on an NC3Rs-funded Neuroscience PhD studentship with Dr. Wendy Noble and Dr. Diane Hanger at King’s College London, UK. This studentship enabled me to make steps into the Alzheimer’s disease (AD) field, where I worked on understanding mechanisms underlying the release and spread of the protein tau both in healthy brains and in AD brains.

For the past two years, I have been working as a postdoctoral research associate in Dr. Todd Golde’s laboratory at the University of Florida. My research to date has focused on using viral methods to deliver genes linked to AD to mouse brain slices, which can be kept alive in culture for several months. By expressing these genes, we can now model one of the pathologies which builds up in the AD brain –- tau inclusions and subsequent neuronal death in a system which is much more rapid, reproducible, cost-effective and less variable than methods we had before. My current research focuses on using these mouse brain slices with numerous tau inclusions to begin to identify appropriate therapeutic targets and to examine how this buildup of tau results in the death of neurons.

Personal Story

From an early age I was fascinated by the human body and wanted to become a medical doctor. I thought that every day, as a physician, I would be able to help people and have an impact on their lives. I began to gain an insight into a medical career by shadowing doctors and volunteering at hospitals through various placements I organized. It was during these placements that I began to encounter people with neurodegenerative conditions such as Alzheimer’s disease (AD) and Parkinson’s disease, and became interested in the science of the diseases rather than being a physician. The thinking was that maybe in a laboratory, where I’d be studying these diseases and working towards treatments, would be a place where I could help a lot more people. I entered into a neuroscience program at the University of Manchester, UK, and during my undergraduate training was able to complete a 12-month undergraduate research project. I found that I really enjoyed designing, conducting, and thinking about science experiments in the bigger picture. I immediately knew I wanted to pursue a career in research and study neurodegenerative diseases like AD, which affects so many millions of people worldwide. The next step was studying for a PhD in neuroscience, where I first began to work in research on AD at King’s College London, UK. One of the highlights of my PhD was being invited to the Houses of Parliament to present my research to politicians and being able to advocate for increased investment in dementia research. After completing my PhD, I continue to study AD as a researcher at the University of Florida. I am now in a highly exciting research environment, pushing closer to understanding and treating AD and other neurodegenerative diseases. 

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