Alzheimer’s Telltale Tau

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.

''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.