Action of Neurotrophins May Lead to New Methods of Treating and Screening for Many Diseases—From Alzheimer's to Atherosclerosis to Cancer

Dec 10, 2001

A new mechanism for cell survival and cell death—a paradigm describing the regulation of the growth factors called neurotrophins—has been discovered by scientists in the Division of Hematology-Oncology of the Department of Medicine at Weill Cornell Medical College. Their findings, just published in the November 30th issue of Science, have significant practical implications for possible new treatments and methods of screening for many conditions, ranging from Alzheimer's disease to atherosclerosis.

Neurotrophins are peptide growth factors. They are expressed by, and act upon, many different types of cells, though the Weill Cornell scientists focused mostly on neurons and on cells from blood vessels.

Most growth factors, as the principal author, Dr. Barbara L. Hempstead, Professor of Medicine, explains, exhibit a single action on any given class of cells. Thus, some growth factors cause cells to proliferate; others cause them to die. However, studies by many laboratories have demonstrated that the neurotrophins can have complex, and even opposing, pro-survival or pro-death actions on a single cell type. These observations caused the Weill Cornell investigators to ask how the specificity of action was regulated.

What Dr. Hempstead and colleagues in her laboratory found was that the same class of growth factors, at different stages of their synthesis, can have opposite effects. That is, the initial forms of neurotrophins—or proneurotrophins—bind to a receptor called p75, leading to apoptosis, or cell death. Meanwhile, the mature (cleaved) neurotrophins interact with trk (pronounced "track") receptors, leading to cell survival, and, when blood vessels are injured, to responses to that injury.

The paradox—the new paradigm, Dr. Hempstead says—is that the same class of molecules can have opposite actions, depending on how they are regulated inside and outside the cell. The article in Science sets forth in detail and in specialized language the ways in which this occurs.

Recent studies by Canadian investigators suggest that some proneurotrophins are "upregulated" in neurodegenerative diseases like Alzheimer's. Therefore, Dr. Hempstead's work suggests a potential mechanism by which diseases such as Alzheimer's may progress, as well as potential strategies by which a person's risk for those diseases might be measured, or by which the disease might even be treated. The goal would be to find specific drugs that would lower the levels of proneurotrophins and raise the levels of cleaved neurotrophins in the appropriate parts of the nervous system.

The neurotrophins (molecules that were initially identified nearly 50 years ago by the scientist Rita Levi-Montalcini) can also play a critical role in blood vessels and in the response of a blood vessel to injury. Thus, Dr. Hempstead's findings have important implications for the understanding and treatment of atherosclerosis, as well as for the important field of blood vessel formation, or angiogenesis. To combat atherosclerosis, strategies using neurotrophins could be employed to promote blood vessel growth in regions where the blood supply has been compromised by atherosclerotic disease.

The findings have implications extending also to cancer. To fight cancer, a useful strategy may be to promote the binding of proneurotrophins and p75 receptors in the appropriate tissues—to promote the dying off of cancerous cells. And, in fact, the investigators modified natural proneurotrophin to produce a novel, cleavage-resistant proneurotrophin, suggesting a potential strategy for the creation of a new kind of anti-tumor drug.

The research was generously supported by the Burroughs Wellcome Fund, the American Heart Association, and the National Institutes of Health. Dr. Hempstead says that biotechnology companies have been interested in the work of her lab and others, and have been considering ways of utilizing these findings.

In addition to Dr. Hempstead, the authors—all from the Division of Hematology-Oncology at Weill Cornell—are Ramee Lee, Dr. Pouneh Kermani, and Dr. Kenneth K. Teng.

Weill Medical College of Cornell University, founded in 1898, has long ranked among the leading medical schools in the U.S. From the beginning, the Medical College has followed an educational philosophy that combines a strong basic foundation in the medical sciences with extensive and early clinical training in patient care. Under Weill Cornell's innovative Strategic Plan for Research, its physicians and scientists are engaged in both basic and clinical research in the cutting-edge areas of genetics and gene therapy, neuroscience, structural biology, vascular biology, AIDS, cancer, and psychiatry, among many other fields. Together with Memorial Sloan-Kettering Cancer Center and The Rockefeller University, its close neighbors and affiliates on York Avenue, Weill Cornell forms one of the great biomedical complexes in both the nation and the world.