Slowing Alzheimer’s by Enhancing Cellular Garbage Disposal

Karen Duff, PhD
Columbia University (New York, NY)

Co-Principal Investigators

Natura Myeku, PhD
The Trustees of Columbia University in the City of New York (New York, NY)
Year Awarded:
2017
Grant Duration:
July 1, 2017 to June 30, 2020
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2017393S
Award Type:
Standard
Award Region:
US Northeastern

This Alzheimer’s Disease Research Grant is made possible in part by support from Lois and Duane Luallin in Memory of Denver E. Perkins and Edwin H. Luallin.

Karen Duff, PhD

Tau Propagation and Proteasome Mediated Clearance

Summary

There is currently no cure for Alzheimer’s disease (AD). We have identified a new way to treat the disease which is based on stimulating the brains own “garbage disposal units” to remove the toxic proteins that form clumps in the brain, ultimately leading to memory loss. Using a drug we know can target the garbage disposal system of the brain, we will test the effectiveness of this treatment in a model of AD.

Details

The brain of a patient with Alzheimer’s disease shows two abnormalities--clumps of a protein called amyloid into what are known as amyloid plaques, and clumps of a protein called tau into what are known as neurofibrillary tangles. One of the features of Alzheimer’s disease is that the tangles start in one part of the brain (areas involved in memory and learning), but they infect new regions and spread through the brain, contributing to the worsening of the disease.

We have spent several years studying how the tangles spread through the brain and what effect tangles have on brain function. We have recently described a way to prevent tangles forming in the brain by enhancing a molecular method known as “clearance,” which is a natural way that brain cells remove (“clear”) toxic or abnormal proteins. We have identified several drugs that can boost clearance and improve the brain’s ability to clear abnormal tau thereby removing tangles. While we have been able to clear tangles to some extent at various stages of the disease in a mouse model, we have not yet shown whether these drugs can prevent the spread of the tangles within the brain. This could be very important if we want to prevent tangles from taking hold or making the disease worse.

Using a new mouse model, we propose to test whether the spread of tangles through the brain is a result of abnormal tau overwhelming the cell’s ability to clear it and whether we can boost cell defenses against tangles using clinically approved drugs that have not been used for this purpose previously. If our drugs do prevent the spread of tangles through the brain by enhancing clearance, they would be good candidates for a clinical trial in AD patients, as well as in patients suffering with tangles that cause a different dementia known as frontotemporal dementia (FTD).

About the Researcher

Dr. Duff is professor of pathology and cell biology at Columbia University. After receiving her PhD from Sydney Brenner’s department at the University of Cambridge in 1991, she undertook postdoc positions in London with Alison Goate (1991-92) and with John Hardy at the University of South Florida (1992-94). She joined the faculty at the University of South Florida, then became an associate professor at Mayo Clinic in Florida. She joined the Nathan Kline Institute in New York in 1998, serving on the NYU faculty until joining Columbia in 2006. In her translational research program, Dr. Duff has created several transgenic mouse models for Alzheimer’s disease (AD) to explore disease mechanisms and test therapeutic approaches.  Her current interests are in exploring the role of the risk factor ApoE4 in AD pathogenesis, exploring the mechanisms and circuitry involved in spread of disease within the brain, and identifying the role and therapeutic potential of autophagy and proteasome-mediated clearance to remove pathological proteins. Dr. Duff has published more than 120 peer-reviewed research articles and received a number of prizes, including the Potemkin Prize in 2005.

Personal Story

I was born to a doctor father and nurse mother, who instilled in me a desire to help people from a very young age. I was always interested in biology but found it too vague to answer questions precisely.  As a young teenager my favorite subject was physics, as I loved how mathematical principles could be directly translated into phenomena that shape our world. But physics did not address my need to help people. When I was 16, I went to my first lesson on genetics and I was stunned to hear that a single DNA base change in 3 billion bases could give you a disease. It was at that moment that all of my favorite things-- precision, biology and human need--came together and I knew I wanted to make a career of understanding diseases at the molecular level. My performance in high school and as an undergraduate was not stellar, as studying didn’t fit in too well with enjoying my young adult life. Fortunately the English education system was forgiving, and I finally found my passion when I started my PhD work, looking at genetic causes of cardiac defects in Down syndrome. From there my post-doctoral work moved to the brain, to Alzheimer’s disease, and to genetic engineering. I loved to be able to make a very precise and defined change in the DNA and then follow what happened in multiple systems, from single cells to a living animal. I allowed the transgenic mice to lead me in many different directions, which caused problems as a new assistant professor trying to find a fundable niche, but it gave me a breadth of experience that I have tapped into as an older researcher. Luckily, several of my mouse models were popular and I had the opportunity to collaborate widely. I now find that this broad experience allows me to link ideas and observations together to have better insight into the disease, and enabled me to address technical challenges and limitations using a wide range of tools, some of which have not been applied to studies of neurodegenerative disease. For the later stages of my career, I have been thinking about therapeutic targets and the development of new drugs. I hope these will lead me to fulfill one of my lifelong goals: eradicating a human disease.  

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