Einar M. Sigurdsson, Ph.D., explains a vaccine that could be used to prevent Alzheimer's disease.
You are working on a vaccine specially aimed at tangles of TAU -- Could you explain what it does and how it works?
Dr. Sigurdsson: Yes, the vaccine is basically a small peptide that is derived from the pathological TAU protein. When we inject it into animals with an immunostimulatory compound, they make antibodies against this peptide. These antibodies then get into the brain of the animals, into the neurons and they clear the aggregates of pathologic TAU protein inside them.
What is TAU protein and how is it related to Alzheimer's?
Dr. Sigurdsson: In normal conditions, the TAU protein is involved in facilitating transport of chemicals within the neurons and maintaining the structure of the neurons. But under pathological conditions, such as in Alzheimer's disease, the TAU protein aggregates within the neurons and deposits into tangles and eventually leads to the death of the neurons. By using this approach to harness the immune system of the body to make antibodies, we can target the disease form of TAU. We can then clear these TAU aggregates from the neurons and we hope this can be used in Alzheimer's disease as well. It is working very well in the animal models.
What are the animal model results?
Dr. Sigurdsson: There is a behavioral improvement in these animals. The initial model that we used has a lot of TAU aggregates in the spinal cord, brain stem and the hippocampus that causes motor impairment, which is not something you see in Alzheimer's disease but it still a useful model to test initially. We see that the animals improve and can perform a motor test much better than the control animals. When we look at the brains of these animals, there is a clearance of the pathological TAU. Now, we are following up on those studies in different tangle models that do not have motor impairments but resemble Alzheimer's disease -- that is they have cognitive impairments. In our preliminary findings that are not yet published, we are seeing cognitive improvements in those animals with the same vaccine.
What is an aggregate?
Dr. Sigurdsson: An aggregate is a clump of TAU protein. Several of the TAU proteins clump together and form insoluble aggregates. These clumps of protein end up in the cell body and clog up the pathways in the neuron, killing it. Neurons within the memory region of the brain, the hippocampus, are very prone to develop clumps of TAU protein.
What does TAU do in a person with Alzheimer's disease?
Dr. Sigurdsson: They correlate very well with dementia -- the more you have of these TAU aggregates, the more severe your dementia is. They actually correlate much better with dementia than amyloid beta plaques.
What could the vaccine mean for Alzheimer's patients?
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Health Beat
Experts say they may have created a vaccine that could prevent Alzheimer's disease.
 
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Dr. Sigurdsson: Assuming the safety profile of this approach will be good, this could mean a novel therapy for Alzheimer's disease. But of course, this has to be tested more thoroughly in different species prior to doing human trials. We now have very good data from rodent animal models, but we would have to test this further in other species and do a thorough toxicological analysis of the animals. But so far, we have not seen any toxic effects in the animals with this approach.
How would the TAU vaccine work in humans?
Dr. Sigurdsson: You would get an injection under the skin, probably a few injections, that would cause you to make antibodies. Antibodies would get into the brain, clear the TAU aggregates and your memory would improve. Or, they would prevent further deterioration of the memory. This could also be achieved by administering antibodies directly, and that would mean more injections, probably several times a year, to maintain a high level of antibodies.
What is the vaccine made of?
Dr. Sigurdsson: This particular vaccine is made up of a small fragment of the TAU protein that is very immunogenic, meaning it elicits a good antibody response. It's recognized as a structure that your immune system makes antibodies against very easily. We also changed it a little so it looks more like the pathological version of TAU protein so it would target the pathological TAU rather than your normal TAU protein.
What are some of the potential risks of the vaccine?
Dr. Sigurdsson: There is always the possibility you are actually making antibodies against your own normal protein, so there is a risk of autoimmune disease. But by targeting the pathological TAU protein, we think it's unlikely this would happen. There is one issue that we have noticed in the animals that may actually diminish this risk -- in a normal individual, antibodies do not pass through the blood brain barrier, which is what controls the access of chemicals to the brain. But in the pathological condition, such as in Alzheimer's disease, there is an inflammation in the brain and this barrier is not as good so the antibodies get in more easily. This means under normal conditions, the antibodies would not access the brain -- only under pathological conditions. Therefore, once you start to develop Alzheimer's disease and the barrier breaks down, you would have antibodies available in the bloodstream to get into the neurons and clear the TAU aggregates.
Is there currently anything to slow Alzheimer's progression or reverse the disease?
Dr. Sigurdsson: There is certainly nothing that reverses Alzheimer's disease. The compounds that are on the market may slow the progression slightly but that has been debated. They primarily work in the early phases, but there is nothing now that can either prevent Alzheimer's disease or dramatically improve the cognition in patients that have it.
What potential does this line of research represent have?
Dr. Sigurdsson: Most of the ongoing studies now are tied to the amyloid-beta peptide but there are very few studies targeting TAU. The main reason for this is that it is a difficult protein to target because it is inside the neurons, whereas most of the amyloid-beta protein is outside the neurons. This represents a novel approach that has potentially substantial therapeutic implications.
And one of those potentially substantial therapeutic implications is that it can actually reverse the pathological process?
Dr. Sigurdsson: Yes. We don't know the details of the degree of reversal because we start to treat the animals when they are in the early stages of the pathology, but in ongoing animal studies we are looking to see if this could actually reverse a full blown pathological state. That is less likely though because preventive measures are usually much more effective.
How long might it be until human clinical trials start?
Dr. Sigurdsson: I would say five to ten years because we have to do extensive toxicological studies in other species prior to human trials, but I would hope that we could begin within five years, if we can obtain necessary funding.
What do you see as being the unique significance of your work?
Dr. Sigurdsson: This is the first approach showing the effectiveness of immunotherapy targeting the TAU protein. There are two main proteins that cause Alzheimer's disease -- amyloid beta peptide and TAU -- and this approach targets one of them. Because these two proteins interact, clearing the TAU protein actually reduces the toxic affect of beta amyloid as well. This could mean a better therapy for Alzheimer's disease.
Has there been research showing the effectiveness of immunotherapy on amyloid beta?
Dr. Sigurdsson: Absolutely. Several studies have shown the effectiveness of immunotherapy on amyloid beta and there are now several clinical trials for that approach. Immunotherapy targeting the disease related forms in Alzheimer's disease is a very promising approach.
