Enzyme Can Repair Alzheimer's Tangles

Release Date:
Alison Davis, NIGMS

Alzheimer's disease is the most common cause of dementia in older people, affecting an estimated 4 million people nationwide.* As the disease progresses, nerve cells and the connections between them are gradually lost, which disrupts key brain functions. Hallmarks of Alzheimer's disease are abnormal brain tissue structures called plaques and tangles. Scientists have linked the appearance of tangles with memory loss and other symptoms of dementia. Researchers suspect that the tangles--basically knots of a long, stringy protein called "tau"--critically compromise the normal functioning of nerve cells by crippling their ability to communicate with neighboring cells. Normally, tau's job is to both assemble and maintain the cell's scaffolding apparatus (groups of proteins called microtubules) that stretch from one end of a nerve cell to another and ferry nutrients and structural components. Tau gets into trouble and cannot keep its proper structure, scientists believe, when it acquires too many molecules of a chemical tag called a phosphate.

Now, a basic researcher studying the process of cell division has identified an enzyme that, in a test tube, can coax the phosphate-laden tau jumble back to its normal shape. Dr. Kun Ping Lu of Harvard Medical School found that the enzyme, dubbed Pin1, somehow rehabilitates tau proteins so that they in turn can properly assemble microtubules side by side into the threadlike shape that forms the cellular scaffold. Interestingly, tissue inside the brains of people with Alzheimer's disease is conspicuously short of available Pin1, because Pin1 is apparently depleted by working overtime to keep fixing tau. These results lead the researchers to believe that this critical enzyme somehow is unavailable to repair tangles as they form.

Pin1's detangling job is not limited to the brains of people with Alzheimer's disease. The enzyme also juggles phosphate-tagged proteins that regulate the timing of cell division in many different cell types. The discovery of the healing power of Pin1 in nerve tissue may aid in researchers' quest for new therapies to treat Alzheimer's disease and other so-called neurodegenerative diseases that disable the brain.

*National Institute on Aging, 1998 Progress Report on Alzheimer's Disease.


Lu P-J, Wulf G, Zhou XZ, Davies P, Lu KP. The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature 1999;399:784-8.

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