Biomedical Frontiers: SPRING/SUMMER 1997, Vol.4, No.3
Special Section: Alzheimer's Research
Of Microtubules, Neurofibrillary Tangles, and Phosphorylation

Researching Alzheimer's Disease by Michael Shelanski, M.D., Ph.D. Delafield Professor and Chairman,           Department of Pathology Co-Director, Taub Center for           Alzheimer's Disease Research Alzheimer's disease is the fourth leading cause of death in this country, affecting more than 4 million people. In 1991, it cost an estimated $70 billion a year to care for people with Alzheimer's. That figure is now estimated to be $101 billion. Researchers at CPMC are dedicated to mitigating the medical, social, and economic impacts of this devastating disease. The Taub Center for Alzheimer's Disease Research at Columbia University is one of 15 NIH-sponsored centers in the United States. Started just eight years ago, the center is now one of the best in the country. One of the unique aspects of the center is that it brings together a combination of scientists from a wide range of disciplines, all dedicated to one objective: eradicating and attacking Alzheimer's disease. This issue of Biomedical Frontiers offers a brief glimpse at some of the research at the Taub Center.

Are the lesions of Alzheimer's disease due to a microtubule defect? Two CPMC labs working on the different sides of the same coin offer intriguing evidence of this possibility.

Drs. Gregg Gundersen, associate professor, and Ronald Liem, professor, in pathology and in anatomy and cell biology, are focusing on the role of phosphorylation, microtubules, and the health of neurons. Dr. Gundersen studies phosphatases; Dr. Liem, kinases.

Experiments in Dr. Gundersen's lab have focused on understanding how microtubules change from a dynamic to a stable state, which seems to occur during differentiation of neurons and other types of cells. His studies have shown that one of the critical factors regulating microtubule stability is one of a group of enzymes known as protein phosphatase. The effect of phosphatase inhibitors on stable microtubules suggested that one of the protein phosphatases might be right on the microtubules, and additional experiments have borne this out. The findings are important to Alzheimer's disease because tau, which makes up the paired helical filaments of neurofibrillary tangles, one of the characteristic deposits in Alzheimer's disease brain tissue, is a microtubule-associated protein.

"In these filaments, tau has an abnormal level of phosphate," says Dr. Gundersen. "Phosphatases on microtubules would be a good candidate for regulating tau phosphorylation."

Dr. Gundersen and colleagues are now trying to understand how phosphatases, at a molecular level, associate with microtubules. One theory is that regulating proteins bind to the phosphatase, and this allows the phosphatase to associate with the microtubule. In the absence of such a regulatory subunit, or if the regulatory subunit were defective, the phosphatase would not be able to associate with the microtubule, and abnormal tau phosphorylation would result. This could have drastic consequences, since hyperphosphorylated tau might not stabilize the microtubule.

"Without microtubules, neurons are probably not healthy, so one of the lesions in Alzheimer's disease may ultimately be a microtubule defect," says Dr. Gundersen. He and his colleagues will soon begin investigating this possibility in Alzheimer's tissue.

The other side of the question is what kinase or kinases phosphorylate tau in the brain, an event that may lead to the formation of the paired helical filaments in Alzheimer's disease. Dr. Liem's lab studies CDK5, one of the kinases known to phosphorylate tau, and is investigating specific functions of CDK5 in the brain. (CDK5 has been shown to have kinase activity only in the brain, although it is also present in other tissues.) To understand the function of CDK5 specifically in the nervous system, Dr. Liem and colleagues are working on an animal model in which CDK5 is disrupted by expressing an inactive kinase in high amounts in the nervous system of transgenic mice. The inactive kinase functions as a nervous system specific dominant negative inhibitor and helps elucidate the targets of CDK5 in the nervous system.

In other studies, Dr. Liem's laboratory is investigating what happens if CDK5 is overproduced in transgenic mice. Animal models for these studies will reveal what the natural substrates of CDK5 are in the brain and what kind of pathology the lack of phosphorylation of these substrates will cause in the animals. One question of particular interest to Alzheimer's disease will be whether tau phosphorylation is affected and what the under phosphorylation or over phosphorylation of tau will do to microtubule stability. These studies may help answer the question of whether the lesion in Alzheimer's disease is due to a microtubule defect.