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.
