The New Rage Over Celluar Dysfunction
Researchers Target Molecule Central to Cell Damage in Diabetes, Cancer and Alzheimer’s
New York, NY - August 14, 2000 - In certain illnesses, such as diabetes, cancer, and Alzheimer's, molecular interactions speed up and intensify the process of cellular damage and destruction. Columbia researchers have identified a target, called RAGE, that may allow them to halt this process in its tracks.
The target is a molecule, the receptor for advanced glycation end products (RAGE), found on the surface of many types of cells. RAGE allows cells to sense and respond to environmental cues. RAGE interacts with several different types of molecules, termed ligands, in both health and disease. These ligands include inflammatory mediators, molecules present in tumors, factors found in the bodies of people with diabetes, and fibrils of the type that accumulate in Alzheimer's disease. During the course of any of these disorders, accumulation of the ligands causes a cell to produce more RAGE molecules. This intensified ligand-RAGE interaction drives the disease process forward, resulting in an ascending spiral of cellular dysfunction.
Drs. Ann Marie Schmidt and David Stern and their colleagues identified RAGE in 1992. They have been studying the molecule and its function and have found in a number of animal and laboratory studies that blocking RAGE can halt and in some cases reverse cellular damage.
RAGE plays a central role in the development of diabetes complications, which include heart and blood vessel disease and nerve damage. In diabetes, a person does not produce enough insulin or is resistant to the effects of this hormone, which assists in the normal metabolism of glucose, so diabetic individuals tend to have high blood sugar. Proteins and fats exposed to this sugar undergo a process called glycation and oxidation. The resulting changed proteins and fats are called Schiff bases and Amadori products. Formation of these materials can be reversed, but they may undergo a further series of reactions, resulting in the formation of advanced glycation end products (AGEs). AGEs cannot be converted back into normal fats and proteins, and they tend to accumulate in the bodies of people with diabetes.
Drs. Schmidt and Stern have found that RAGE expression is heightened in certain cells known to become dysfunctional in diabetes, including smooth muscle cells, immune system cells called mononuclear phagocytes, and endothelial cells. They believe that the interaction of AGE with RAGE initiates a series of events leading to a change in cellular function.
The researchers also have found a way to block this interaction: by introducing "decoy" RAGE into cells. This decoy, called soluble RAGE (sRAGE), consists of the outer two-thirds of the RAGE molecule. Since it is not attached to a cell, sRAGE can bind to AGEs without initiating cellular changes.
In 1998, the researchers reported that they were able to prevent the development of atherosclerosis in diabetic mice by administering sRAGE. They also found beneficial effects of blocking RAGE in animal models of diabetic periodontal disease and wound healing. Dr. Schmidt said, "We are working hard to extend our concept of RAGE blockade to other complications of diabetes and hope that this approach could prevent the progression and even induce regression of such complications."
The team’s most recent discovery, reported in the June issue of Nature Medicine, was of a close association between RAGE expression and amyloidosis. Amyloidosis occurs when abnormal proteins called beta-sheet fibrils accumulate outside healthy cells, forming plaques that displace and damage normal tissue. This occurs in many types of chronic illness, including Alzheimer’s disease, leprosy, and tuberculosis.
When a type of protein called amyloid A interacted with RAGE, the researchers found that fibril formation was accelerated, normal cellular structures were displaced, and cellular dysfunction resulted. And in tissue from a patient with system-wide amyloidosis, the researchers found heightened production of RAGE as compared with spleen tissue from a healthy individual of the same age. They also found that by blocking RAGE, they were able to suppress cellular stress and prevent amyloid deposits from forming in the spleens of mice genetically engineered to develop amyloidosis in this organ and given medication to accelerate this process. This suggests that blocking RAGE could prevent the accumulation of fibrils that leads to amyloidoses, including Alzheimer’s.
The researchers hypothesize that in diseases such as Alzheimer’s a normal inflammatory response initiated by the interaction of RAGE and a ligand becomes destructive. Dr. Stern said, "We hope that blocking access of ligands to the increased levels of RAGE present in the brains of patients with Alzheimer's disease will provide a new therapeutic target to prevent neuronal injury in this devastating neurodegenerative process."
Drs. Stern and Schmidt are continuing their studies of RAGE and have begun planning clinical studies of the molecule.
The research was supported by The United States Public Health Service, The National Institutes of Health, The National Heart Lung and Blood Institute, The Burroughs Wellcome Fund, The Juvenile Diabetes Foundation International and The Columbia University Department of Surgery.