Fall 1994 Volume 3, Number 4
A Common Mechanism in Alzheimer's and Adult-Onset Diabetes
by Bruce A. Yankner, M.D., Ph.D.
Dr. Yankner. In background, protein fibrils that may contribute to Alzheimer's and adult-onset diabetes. (Photo by Liza Green, HMS Media Services.)
What do Alzheimer's disease and adult-onset diabetes mellitus have in common? Alzheimer's disease typically begins with the insidious onset of forgetfulness and eventually results in the loss of reasoning, judgment and language abilities. Adult-onset diabetes begins with elevated blood sugar and can eventually lead to loss of vision, loss of sensation, strokes and heart disease. The causes of these two diseases, which together afflict over 10 million elderly Americans, are unknown, and there are no curative treatments.
Although the clinical symptoms of these diseases are different, they have one feature in common. Both accumulate amyloid, an abnormally folded protein which forms fibrils. Fibrils are abnormal strings of proteins clumped together; the fibrils accumulate because they are difficult for the body's natural defenses to remove. In Alzheimer's disease, fibrils made of a small protein called §-amyloid are formed in the brain. In adult-onset diabetes, fibrils made of a different protein, called amylin, form in the pancreas.
In the late 1980's, it was widely believed that §-amyloid was not the cause of brain degeneration in Alzheimer's disease. At that time, our laboratory performed a series of studies which demonstrated that when §-amyloid is added to cultures of brain neurons, the neurons eventually die. Many laboratories have confirmed this observation and, along with our own, have demonstrated that §-amyloid kills neurons most effectively when it forms protein aggregates similar to those that form in Alzheimer's disease.
Based on our finding that §-amyloid is toxic in the brain, we wondered whether the amylin protein that forms fibrils in diabetes might be toxic, causing cell death in the pancreas. To address this question, we developed a system for keeping insulin-producing cells, called islet cells, alive in cell culture after surgically removing them from the pancreas of an adult rat. We found that addition of amylin caused the gradual degeneration and death of these islet cells.
Insulin-producing cells growing together in an islet after removal from a human adult pancreas. Isulin stained in red. (Courtesy of Dr. Yankner.)
Addition of amylin results in widewread islet cell degeneration and insulin depletion. (Courtesy of Dr. Yankner.)
Furthermore, the degeneration of insulin-producing cells was observed only when amylin formed fibrils, as occurs in the diabetic pancreas. When the amylin proteins were kept from forming fibrils, as in a normal adult pancreas, the insulin-producing cells remained alive and appeared normal.
The amylin fibril caused a specific type of cell death that the body uses to eliminate excess cells during development or malfunctioning cells in the adult. This process is called apoptosis and occurs when cell suicide genes are triggered, causing the cell to break apart and die.
We observed that when the amylin fibril contacted the cell surface, it triggered these suicide genes in the insulin-producing cells. Perhaps the amylin fibril interferes with the normal function of the cell, and this is a normal way for the body to eliminate these malfunctioning cells. However, if too many insulin-producing cells are lost in this manner, diabetes may develop. How does this process get started? It is widely believed that adult-onset diabetes begins when tissues become resistant to insulin, due to obesity or the inheritance of particular genes. To compensate, the pancreas produces more insulin. But whenever insulin is produced, amylin is produced as well. So the pancreas starts to accumulate amylin. Our results suggest that when a critical level of amylin is reached, amylin fibrils begin to form and may cause dysfunction and the death of the insulin-producing cells.
In Alzheimer's disease, a similar scenario may occur. Unknown environmental factors are suspected of playing a role in causing the §-amyloid fibrils to form in the brain. In addition, several genetic factors have been identified that may also promote the formation of the fibril, including mutations in the amyloid protein and a variant of another protein called apolipoprotein E. All these different causes may lead to a common final result, the formation of §-amyloid fibrils and the death of brain cells leading to dementia.
An exciting prospect resulting from these studies is that Alzheimer's disease and adult-onset diabetes may be treated by preventing the formation of amyloid fibrils. Furthermore, it is possible that a drug which prevents fibril formation may be therapeutically effective for both diseases.
We are currently testing a candidate agent which inhibits fibril formation from both the Alzheimer and diabetic proteins in test tube experiments, and hope that analogs of this agent may hold therapeutic promise.
Perhaps the most fundamental approach is to understand why the abnormal fibril forms. Alzheimer's disease and adult-onset diabetes both occur late in adult life, and it is possible that the fibril is part of an accelerated aging process. For example, an increase in age-related chemical alterations of proteins could make the amyloid proteins stick together and form fibrils. Further research into the basic mechanism of this process may lead to the eventual treatment of these devastating diseases.
