by Kirsten Rohde
When people think of medical research, they often imagine scientists in lab coats peering at petri dishes through microscopes. Yet what generally makes news about Alzheimer’s disease (AD) are the studies conducted with human participants, the clinical trials of promising new drug treatments. Both are important aspects of research and both can ultimately lead to the development of new treatments or even a cure for AD.
But what is going on in those labs? How does laboratory research lead to treatments for AD?
One laboratory at the University of Washington Alzheimer’s Disease Research Center (UW ADRC) is looking at an organism very different from humans: a worm known as C. elegans. This round worm is less than one tenth of an inch long. It is barely visible to the naked eye, and its natural habitat is often the compost pile. Yet this tiny worm has about sixty percent of the same genetic material as humans, and that’s the start of the story about how laboratory research might eventually lead to new treatments for dementia.
To find out more, I met with Brian Kraemer, PhD, a UW ADRC research biologist at the VA Puget Sound Health Care System (VAPSHCS) and Research Assistant Professor at the UW. Dr. Kraemer leads a research group focusing on the most fundamental causes of neurodegeneration in AD and related disorders. His research program is funded by three grants, one of which is from the Western and Central Washington State chapter of the Alzheimer’s Association.
Dr. Kraemer first became interested in research on disorders of the nervous system when he was doing graduate work. He came to Seattle to work with Gerard Schellenberg, PhD, a geneticist affiliated with the UW-ADRC for many years. Dr. Kraemer wanted to focus his research work in the area of human neurodegenerative diseases, both because of his professional interest and for personal reasons—some members of his family have had Alzheimer’s disease.
“When I came to the Schellenberg lab,” he explains, “like most postdoctoral students, I focused on a number of different research areas. One of them was working to set up a model for using C. Elegans to study the tau pathology that causes neurofibrillary tangles in the brain neurons of people with AD. This research took off and became the focus of my current work.”
Research into the causes of AD and other dementias begins by looking at what is going wrong in the brain tissue of affected people. The brains of people with AD have two types of distinctive changes: the development of neurofibrillary tangles, which are twisted strands of a protein called tau that is found inside brain cells (neurons), and senile plaques, which are complex deposits of amyloid and other proteins in the brain but outside of the neurons. The research conducted in laboratories such as Dr. Kraemer’s is research that occurs at the level of DNA and the proteins within cells. This type of research works to re-create those AD-related changes to neurons seen in humans so that experiments leading to possible treatments can be conducted. Researchers do this by using simpler organisms that can be studied more quickly and in larger numbers than research with human participants.
C. elegans has the experimental advantage of being a very simple organism: they reproduce quickly, with a new generation about every three days, and you can see inside of them while they are still alive. Moreover, there are only 302 neurons in the adult C. elegans, whereas the number of neurons in humans is estimated to be as many as one hundred billion. In contrast to mice or humans, the nervous system of C. elegans has been completely mapped out.
Dr. Kraemer explains that “we take the human tau gene that has a dementia-causing mutation in it and put it into the worms so that the worms ‘express’ the human tau in their neurons. In other words, we create a situation where we can see what happens if they have the same abnormal tau in their nerve cells as do humans with AD. When we do this, the neurons stop functioning normally, which in a worm shows up as problems with moving—they become slowed down and uncoordinated. When we look biochemically at the worms, we also see some other changes that are similar to what we know happens in the brain cells of humans with dementia.”
Using this model, it then becomes possible to experiment with ways to make the worms well again. One way that Dr. Kraemer and his staff approach this is by deleting genes and then searching for worms that appear to be resistant to the ill effects of the mutated tau that has been placed in them. In other words, watching under a microscope to see if the worms start moving normally. This allows the researchers to identify particular genes that when deleted from the worms (“knocked out”) allow the worms to remain unaffected by the toxic effects of the tau mutation. Dr. Kraemer and his staff have found two such genes, and one of them has a related gene in humans (mammalian SUT-2). The theory is that this gene may prevent the breaking down of abnormal proteins and may thus allow further damage to occur to the nervous system.
The next phase of Dr. Kraemer’s research is the area of study that is funded by the Alzheimer’s Association local chapter. “We’ve taken a collection of drugs that are not patented anymore, drugs that have already been tested and approved for humans for all sorts of medical conditions,” he explains, “And we’re looking to find a drug that makes the worms better. So we will systematically test every one of about 1,100 drugs in the worms and then, by observing them under the microscope, we will see if they get better. If so, we can narrow our search and focus on the drugs that show improvement in the worms. Our ultimate goal is to find drugs that prevent tau pathology and may lead to the development of a treatment for tau pathology (that is, neurofibrillary tangles), in AD.”
In talking with Dr. Kraemer and in having a chance to look at these little worms under a microscope, I became aware of how much time and effort goes into the search for possible treatments, even at this earliest phase of developing a model in worms and then trying to find out more about the genetics. With the support from the Alzheimer’s Association grant, Dr. Kraemer and his colleagues can now take the next step and search for possible drugs that may make a difference in worms. A drug discovery in the worms could then be applied to higher animals, and eventually to people who suffer from AD. Kraemer is appreciative of the enthusiasm and support of the Alzheimer’s Association for his research—“If this research were to pan out,” he says, “It would be fantastic.”
Dr. Kraemer’s research program is currently funded by three grants: