A single mechanism involving a brain chemical may underlie the known abnormalities that characterize Alzheimer's disease and hold the key to possible treatment, researchers working at MIT have reported.
Their article in the October 9 issue of the journal Science suggests that treatment using drugs which act like or increase the amount of the brain chemical acetylcholine might slow the onset of Alzheimer's. The devastating brain disease, which causes dementia and leads to death after 6 to 10 years of steady mental decline, affects about 4 million people in the United States, most of them elderly.
The Science article was written by Roger M. Nitsch, Barbara E. Slack, Richard J. Wurtman and John H. Growdon. All are connected with the MIT Clinical Research Center, which is directed by Professor Wurtman, and with the MIT Department of Brain and Cognitive Sciences. In addition, Dr. Growdon is the Program Director of the Alzheimer's Disease Research Center at Massachusetts General Hospital's Department of Neurology where Dr. Nitsch is a research fellow.
The research was supported by grants from the National Institute of Mental Health and the National Institute on Aging.
The paper in Science reports that the brain chemical acetylcholine has a major effect on the way the body metabolizes a protein, amyloid precursor protein (APP).
The accumulation of abnormal proteins, particularly amyloid, is one of the major abnormalities found in the brains of Alzheimer's victims. Other abnormalities include: a reduction in the amounts of acetylcholine because of the loss of nerve cells which contain this transmitter; and disturbances in the metabolism of choline, acetylcholine's precursor.
Dr. Wurtman said he and his colleagues think the neurochemical abnormalities in Alzheimer's disease are related in this way: 1) there is damage to certain acetylcholine-releasing neurons, and 2) this leads to a reduction in acetylcholine release, and in the breakdown of APP to harmless fragments and, correspondingly, to an increase in the formation of fragments that can form amyloid.
The body deals with APP in one of two ways. One way yields harmless fragments, causes no problems, and is stimulated by acetylcholine, the researchers said. Their paper is the first to describe this stimulation function.
The other way APP is metabolized results in insoluble rock-like fragments that the body can't get rid of.
"It is well known that acetylcholine is especially deficient in brains of people with Alzheimer's disease," said Professor Wurtman, MD, in commenting on the paper in Science.
"So we speculated that, because of this deficiency, APP metabolism takes place in a way that yields the fragments which go to make amyloid," Dr. Wurtman said.
Dr. Nitsch said that because there are few amyloid deposits in healthy brains, "we figured that the harmless processing pathway of the amyloid precursor prevails under healthy conditions, and that in Alzheimer's disease there may be a shift towards the processing pathways which yield the fragments from which amyloid is made."
To test whether neurotransmitters, whose chief function is to permit communication among nerve cells in the brain, promoted processing of the amyloid precursor, the research team cultured human cells which contained both the human amyloid precursor and the human neurotransmitter receptors for acetylcholine.
Stimulated neurotransmitter receptors secreted 4 to 5 times more amyloid precursor products than unstimulated cells, the researchers report.
"The effect was very fast, as it happened within minutes after stimulation of the neurotransmitter receptors, suggesting that the biochemical mechanism necessary for cleavage and secretion is readily turned on by the activated neurotransmitter receptors," Dr. Nitsch said.
"This observation showed for the first time that neurotransmission and amyloid precursor processing are related biochemical events," he went on, saying that the results suggested a novel function of neurotransmitters: "They can control cleavage and secretion of a protein, which, if unchecked, can yield dangerous amyloid fragments."
"The results of this study suggest potential ways to treat Alzheimer's disease using drugs to prevent the buildup of amyloid in the brain. One possible approach might be the use of drugs designed to enhance normal amyloid processing. Another strategy would be drugs that inhibit amyloidogenic processing," he said.
A version of this
article appeared in the
October 21, 1992
issue of MIT Tech Talk (Volume