Tau: Killer of Cognitive Thought

Many neuro-degenerative diseases are a cause of aging. While memory loss is usually associated with neuro-degenerative diseases, it is, in fact, the cause of normal degeneration of the brain and formation of hard clusters of dying neurons, known as senile plaques; an increase in decayed dentricles – neuro-fibrillary tangles; and chemical interactions in the brain rather than the death of neurons. Long-term memory loss occurs in patients with neuro-degenerative disease long before the causes of the disease remotely reach the ability to kill brain cells.

One of the most devastating neuro-degenerative diseases in the United States today is Alzheimer’s disease. “Alzheimer’s is the eighth leading killer in the nation today,” explains Dr. Chris Gamblin, PhD, professor at the University of Kansas and project leader of The Role of Tau in Alzheimer’s and Other Neuro-degenerative Disorders.

“About 20 to 30 million people today suffer from mild-cognitive impairment and about 70 percent of those 20 to 30 million will have at least a small case of Alzheimer’s disease2.” Alzheimer’s patients tend to live shortened lives caused by secondary effects of the disease. For example, a woman with Alzheimer’s disease may lose her ability to swallow correctly and develops pneumonia from food entering the lungs, or a man with Alzheimer’s disease loses control of his bladder, which leads to infection. Usually, Alzheimer’s patients pass away from secondary causes of the disease about eight years after being diagnosed.

Gamblin says that, physically, Alzheimer’s disease cannot be confirmed until death and an after an autopsy is performed2. Doctors diagnose Alzheimer’s patients with the disease when the patient displays significant memory loss and one other cognitive disability such as movement, speech, change in behavior, problems performing routine tasks, disorientation, and poor judgment. After death, a doctor’s diagnosis is confirmed by the presence of large quantity of senile plaque and neuro-fibrillary tangles in the micro-tubules of Alzheimer’s patients.

While the cause of Alzheimer’s disease is unknown, many scientists believe that the disease is caused by abnormally polymerized forms of the proteins beta-amyloid and tau2. For a century, Alzheimer’s disease has been studied to determine the causes and effects of the disease on the brain. Until the early 1990’s, before proteins tau and beta-amyloid were discovered to effect cognitive thought, little progress had been made.

Most research being done today regarding Alzheimer’s deals with the effects of beta-amyloid on the formation of senile plaques in Alzheimer’s patients. The majority of multi-million dollar researching institutes dealing with Alzheimer’s and other neuro-degenerative disease focuses their research on the beta-amyloid protein. Therefore, smaller researching institutions develop research projects regarding the effects of tau protein. However, tau protein research may hold as much influence on the disease as beta-amyloid.

Dr. Chris Gamblin’s team, a smaller researching institution, focuses its studies on the polymerization of tau proteins. Even though most people believe that the beta-amyloid protein has a greater effect on Alzheimer’s, Gamblin reveals, “We cannot compete with multi-million dollar corporations researching beta-amyloid. Rather than working on the same research, we are more productive working on a smaller scale with tau protein. I believe that tau protein is leading us in the right direction. I agree that beta-amyloid does have an effect on Alzheimer’s patients, but I believe the key to the problem lies with tau2.”

In a normally functioning human brain, tau is responsible for stabilizing the neuron in micro-tubule nerve cells. Micro-tubules provide transportation to the different parts of the cell. During normal function, tau merely keeps equilibrium within the cell. In an Alzheimer’s patient, tau becomes hyperphosphorylated2 – large amounts of phosphates are introduced to the tau protein – and forms a neuro-fibrillary tangle called abnormally phosphorylated tau (PHFtau). The neuro-fibrillary tangles lose their ability to bind to molecules thus hindering the neurons ability to transfer signals through the cell body.

In a normal functioning neuron (top) tau upholds the micro-tubules in the cell. In a pathological neuron (bottom), the neuro-fibrillary tangles hinder the cells ability to support axonal transportation of molecules throughout the cell. Picture by Ann Thomson5

The research being in Dr. Gamblin’s lab consists of monitoring the effects of the phosphorylation on the polymerization of tau. Polymerized tau protein forms the neuro-fibrillary tangles that turn normally functioning neurons into pathological neurons. Dr. Gamblin says, “Our research is interested in finding out how tau protein connects and polymerizes. If we could find the point at which tau proteins connect and remove this point, we believe we can stop the formation of hyper-phosphorylated tau protein2.”

(Picture by Roger Knowles’ Lab7)

Green – Beta-amyloid peptide (forms senile plaques)

Red – Phosphorylated tau (forms neuro-fibrillary tangle)

Discovering how tau polymerizes and becomes hyper-phosphorylated proves extremely challenging. The problem with Alzheimer’s lies in the fact that the exact cause and effects of the disease are unknown. Gamblin says, “We know so little about the physical side of the disease. For example, senile plaques are present in everybody, but a person with Alzheimer’s has an increase in senile plaques. What this means, we do not know. Also, nobody really knows if Alzheimer’s is the effect of tau polymerization or if tau polymerization is the effect of Alzheimer’s2.”

However challenging the research may be, Gamblin’s team barrels through the research performing a myriad of experimental research. Some of the experimental approaches in Dr. Gamblin’s lab include site-directed mutagenesis, laser light scattering, electron microscopy, and in vitro binding assays. Dr. Gamblin explained each process. Site-directed mutagenesis is used to change specific DNA sequence of a gene.

This is done using a DNA primer and is used on the tau protein to change its polymerization. Then, the tau is monitored to see how and if it polymerizes. Laser light scattering sends light through a mass and can determine the amount of substance. This is used in the laboratory to determine the mass of tau proteins used in each experiment. It is also used to measure the efficiency at which tau proteins bind together to form polymers.

Electron microscopy was used to determine how micro-tubules in the neurons were forming or if they were forming at all. This helps to determine how specific polymers of tau affect micro-tubules and axonal transportation and stability in the cell. Finally, in vitro binding assays were used to measure the number of micro-tubules that bound together with the tau to form stable neurons2.

Speaking of the progress that his team has made toward their goal of discovering the effects of tau and reducing polymerization of tau in the brain, Gamblin says, “We still have a lot of work to do. We do not know the effects of tau, nor do we know how tau polymerizes. We still have a lot of work to do.” In an ordinary week, Gamblin says they purify forms of tau every three days. Each day, the team performs a different step of the process using the different techniques described to find the effects of different polymerizations of tau2.

Dr. Gamblin says, “We take our research on a day by day basis hoping that one day we will find what we are looking for.” In terms of what the team will do after their initial research is done, if formation of polymerized tau can be stopped, the team plans on proceeding with research determining the effects of a drug that stops polymerization of tau on the rest of the body. While that seems a chore in itself, research will need to be done to determine how the substance metabolizes.

When drugs are first introduced into the body, the chemicals in the drug take effect. The drug is then metabolized, its chemicals modified, resulting in a chemical that may be toxic. The toxicity of a drug that inhibits the formation of tau polymers will need to be carefully measured in the laboratory before the drug may be released. In addition, drug metabolism allows for a drug-drug interaction or drug-chemical interactions that must also be taken into account when researching the drug. If two drugs or chemicals interact in a destructive manner, the negative consequences of the drug will outweigh the positive effects.

Much work still needs to be done before Alzheimer’s patients and their families can find relief. Scientists still need to find the role of beta-amyloid and tau proteins before they can even identify the cause of Alzheimer’s disease. Then research must be completed to find out how to stop the formation of neuro-fibrillary tangles. Finally, scientists must study the pharmaceutical side of the problem. Along with the drugs, the process of metabolism must be studied to determine how the drug will metabolize in the body. With that said, decades may pass before Alzheimer’s is cured or treated effectively.