Alzheimer’s Telltale Tau

Novel antibodies may aid diagnosis and treatment at earliest stages of disease

Under normal circumstances, the tau protein is a hard-working participant in memory and normal brain functioning.  But as is becoming increasingly evident, in Alzheimer’s disease and other neurodegenerative diseases, tau not only ceases to play a productive role in brain health, but actually undergoes a Jekyll-and-Hyde transformation to become a misshapen villain that destroys brain cells.

Now a novel antibody technology developed by a scientific team at Beth Israel Deaconess Medical Center and Harvard Medical School provides the first clear distinction between two tau isoforms — one healthy and one disease-causing — and demonstrates that only the disease-causing isoform is found in the neurons of Alzheimer’s patients and is exhibited at a very early stage of disease. Described in the March 30 issue of the journal Cell, the findings raise the intriguing possibility that the development of antibodies and vaccines that target only the disease-causing tau isoform could be used to diagnose, treat and potentially even prevent Alzheimer’s before the onset of debilitating symptoms.

Kun Ping Lu, on left, and Xiao Zhen Zhou. Photo by Bruce Wahl

“Since Alzheimer’s disease takes at least a decade to develop, the major challenge to halt memory loss is to identify the initial period when the tau protein is transformed from ‘good guy’ to ‘bad guy,’” said co-senior author Kun Ping Lu, HMS professor of medicine and an investigator in the Division of Hematology/Oncology at BIDMC. “By developing an innovative approach to making antibodies, we have uncovered a new strategy to specifically remove disease-causing tau, while leaving healthy tau intact to carry out its important responsibilities.”

The most common form of dementia in older individuals, Alzheimer’s disease affects 5.4 million Americans and 30 million people worldwide. There is currently no effective treatment for the disease.

In healthy brains, tau serves to both assemble and support microtubules, the “scaffolding systems” that give neurons their unique shape. As part of this normal function, phosphates are routinely added and removed from tau. Phosphates exist in one of two different shapes, or isoforms: The isoform known as trans is in a relaxed shape, while the isoform known as cis is in a twisted shape.

Scientists have known that abnormal phosphorylation of the tau protein is implicated in Alzheimer’s disease and that an enzyme called Pin 1 (prolyl isomerase), originally discovered in 1995 by Lu together with Tony Hunter of the Salk Institute for Biological Studies, protects against the onset of Alzheimer’s in various experimental model systems.

In this new work, Lu and co-senior author Xiao Zhen Zhou, HMS assistant professor of medicine and an investigator in the Division of Hematology/Oncology at BIDMC, hypothesized that when tau is phosphorylated during the normal aging process, it is in the twisted cis shape and that in healthy individuals, the Pin1 enzyme bends the phosphate back into the relaxed trans isoform.  They further posited that when Pin1 is diminished or absent, the untwisting process is disrupted, causing tau to stay in its twisted cis shape — resulting in the development of Alzheimer’s symptoms.

They discovered that although neither isoform is detected in normal healthy brain tissue, the twisted cis tau can be seen in humans with early dementia, also known as mild cognitive impairment. They observed that as early dementia progresses to Alzheimer’s disease, twisted cis tau accumulates only in diseased neurons at the locations that are known to affect memory and the relaxed trans shaped tau isoform does not appear.

Finally, in a series of experiments in the test tube as well as in cell and animal models, the authors demonstrated that increasing Pin1 levels could prevent tau pathology, while reducing Pin1 levels resulted in tau knots and tangles.

— Bonnie Prescott, BIDMC