Why don’t we have Al-zhe answers yet?
Alzheimer’s disease currently affects more than 5 million people in the United States alone. Scientists have studied AD for over 100 years, but the work of all these scientists has not led to a breakthrough yet. As one of these scientists, I am often asked why we don’t have a cure for Alzheimer’s. The answer, in part, is simple: our scientific toolbox is not equipped to study what goes wrong in Alzheimer’s disease.
The physical changes within the brain of Alzheimer’s patients are described by the accumulation of tau. Tau found in healthy brains is shaped much like spaghetti noodles – it doesn’t have a defined shape, instead of taking on many different shapes depending on the environment. Tau found in the brains of people with Alzheimer’s is no longer spaghetti-like and instead is stiff and clumped together. Losing its ability to change shape by clumping and stiffening prevents tau from doing its job, although this change makes the tau easier to study. Our toolbox was developed for proteins that look like rotini -- or clumped spaghetti -- that is, proteins that don’t change shape. Because of the tools we have, scientists know what the clumped tau looks like, but not what healthy tau looks like. We have not been able to watch the change from healthy to unhealthy, which means that we don’t know what causes the change in tau’s shape, how long it takes to change, or if it can be prevented.
The mismatch between the proteins our toolbox was developed to study and the proteins involved in AD has slowed our understanding of the disease. Without basic knowledge about the changes to the shape of tau, it has so far been impossible to make a drug to treat Alzheimer’s disease. Recognizing this mismatch between our tools and the disease, other scientists and I have started developing new tools that were built to study spaghetti-like proteins.
The tool I am developing for spaghetti proteins like tau is called Hydrogen-Deuterium Exchange with Mass Spectrometry, or HDX for short. HDX is like taking a person and spraying them with a hose to see what gets wet. This information tells you what “shape” they are in. If they had their arms crossed, their chest would stay dry. If they were carrying someone on their back, their back would stay dry. If they weren’t paying attention, they would get soaked. A spaghetti protein like tau gets evenly wet when it is healthy because it is constantly changing shape, so no part is protected enough to stay dry. As Alzheimer’s disease progresses and the tau becomes unhealthy, the tau starts to hug itself, and parts are hidden from getting wet. Scientists can create a time-lapse of this information to see which regions of tau clump together first and how long the process takes. We will be able to assess when the changes happened, what caused them, and hopefully, be able to make recommendations for how to keep spaghetti proteins from clumping together.
HDX won’t give us all of the answers about Alzheimer’s disease, but it is a crucial addition to our scientific toolbox, and it could provide us many more answers than we have cobbled together with the wrong tools.
Ellie James is a graduate student in Molecular Engineering who researches tau, a protein that takes on many shapes in healthy individuals, one shape in Alzheimer’s disease, and a unique shape in each other tau-related dementia. Her research will determine what causes tau into specific shapes in disease, which will improve our understanding of how to make medications for dementias.