Discovering the True Nature of Tau to Untangle Alzheimer’s
Tau spreading causes Alzheimer’s symptom development. New science to find and target the toxic form of tau may lead to treatment breakthroughs
Ahead of His Time
In his research more than 100 years ago, Dr. Alois Alzheimer identified three hallmarks of the disease that came to bear his name. In addition to amyloid plaques and brain atrophy, neurofibrillary tangles are characteristic of Alzheimer’s disease. Those tangles are formed when strands of a protein called tau twist abnormally together and prevent proper functioning of neurons.
It would take scientists many decades after Dr. Alzheimer’s work to figure out just how important tau is in the development of Alzheimer’s disease.
“Based on the scientific evidence, we know now that neurodegeneration and the symptoms of Alzheimer’s disease are caused by tau spreading,” says Xavier Langlois, Ph.D., research fellow who leads the team focused on tau at AbbVie’s Foundational Neuroscience Center in Cambridge, Massachusetts, U.S.A. “And while we know how tau’s role in the body, and ultimately, in Alzheimer’s disease starts and ends, we are trying to figure out what happens in the middle that causes tau to turn toxic.”
The Beginning and the Ending
Tau has a very important role in healthy cell function. Tau is a normal, soluble protein that lives in the brain and, like the ties on railroad tracks, its purpose is to help nerve cells transport the materials they need to function. When tau falls off the railroad tracks, as in Alzheimer’s, neurofibrillary tangles form.
Tau starts to build up in the areas of the brain associated with memory and spatial navigation, and once this happens, clinical symptoms of the disease start to occur – symptoms like forgetfulness and sometimes disorientation.
A Frightening Number of Forms
What scientists don’t know is what exactly happens to tau between the time it is functioning normally and when it begins to fall off the tracks.
“We know that at some point, through one process or another, tau takes an insoluble form and begins seeding and spreading throughout certain regions of the brain,” Langlois says. “There is a frightening number of forms of tau that could be the toxic one, and that is the main question we are trying to answer through research – which one is the toxic form?”
After cells make tau, it can be modified in many ways. It can be cut into smaller pieces. Other molecules can attach themselves to tau. Then, individual proteins can start sticking together into larger and larger clumps of tau, accounting for the many different forms tau can take.
Finding the Rest of the Story
Until recently, much of the focus in the discovery and development of new medicines for Alzheimer’s has been the amyloid plaques associated with the disease. Unfortunately, the majority of these approaches have failed to slow progression of the disease in human clinical trials.
“The failure of these approaches has freed the field to embrace and explore new approaches, including tau targeting, and the science is advancing in different ways,” says Lynne Rueter, Ph.D., director of neuroscience discovery at AbbVie.
Having identified that it is tau spreading that causes neurodegeneration, one approach to research includes focusing on targets in the brain that might help to reduce the spread.
Another approach targets tau, itself. “We are trying to stop tau pathology and are testing molecules that isolate and target specific tau forms, as well as those that have pan-tau activity,” Rueter says. “One program at AbbVie is that of ABBV-8E12, an antibody in Phase 2 development that interacts with both soluble and insoluble forms of the protein, which will allow us to see the impact of blocking tau spread on disease progression.”
Impact Beyond Alzheimer’s
Tau is not just found in Alzheimer’s disease. Tau-associated neurodegeneration is found in other neurodegenerative diseases, including progressive supranuclear palsy, Huntington’s disease and others.
“The link between tau and neurodegeneration is so strong that I am 100 percent confident that we have the right target,” Langlois says. “And when we figure out how to target it effectively, we may be able to rewrite the ending of the story for patients with Alzheimer’s disease and beyond.”