Abnormalities Unique to Alzheimer's Are Found


Researchers in an MIT laboratory have discovered chemical abnormalities in the brains of people with Alzheimer's disease that apparently do not occur in the brains of people with other neurologic diseases.

While earlier research has established that two sets of chemical disturbances characterize the brains of those suffering from Alzheimer's, neither of these changes is exclusive to the disease.

The new findings-by researchers from MIT, Massachusetts General Hospital and Boston University, all affiliated with MIT's Clinical Research Center and the MIT Department of Brain and Cognitive Sciences-are reported in the Proceedings of the National Academy of Sciences, a leading science journal.

In an interview, Dr. Richard J. Wurtman, director of the Clinical Research Center, described the discovery as "an important development, with many implications for the development of drugs, including potassium channel blockers that stimulate the release of choline, as well as compounds like CDP-choline that directly enhance the formation of cell membranes."

The abnormalities uncovered in the study involve the way that brain cells use the chemical choline. This chemical is an important building block both for the membranes in brain cells and a neurotransmitter, acetylcholine. Neurotransmitters are the chemicals that carry signals from one nerve cell to another. Choline normally is produced in the liver and obtained from the diet.

The researchers' findings show that choline levels in the brains of Alzheimer's victims are much lower than normal, and the amounts of choline present in the membranes of brain cells are also diminished, partly because the membranes are broken down more rapidly than they should be to release the stored choline.

These disturbances are found all over the brain-both in regions previously known to be involved in Alzheimer's disease and in other regions formerly thought to be normal. Moreover, unlike the other known chemical disturbances of Alzheimer's, they are not found in the brains of people with Down's Syndrome, nor in other neurological diseases like Parkinson's Disease and Huntington's Disease.

Prior to the newly reported discoveries, two other chemical abnormalities had been observed in the brains of people with Alzheimer's. These involved: (1) clumps of proteins, both inside some nerve cells (the neurofibrillary tangles) and in spaces not containing the cells (the "senile plaques," containing a protein mass called amyloid), and (2) decreases in the levels of important neurotransmitters, particularly acetylcholine, resulting from the death of nerve cells containing those neurotransmitters.

These abnormalities are especially frequent in brain regions known to be important for normal memory and learning, like the cerebral cortex, the hippocampus, and certain groups of nerve cells at the base of the brain-in contrast to the newly discovered abnormalities in choline metabolism that seem to be present throughout the brain.

For the study, Dr. Roger Nitsch of the Department of Neurology at Massachusetts General Hospital obtained samples of brains from Alzheimer's patients at autopsy, and compared their chemical contents with those of brains taken from people of the same age whose deaths were not related to brain diseases. He also took care, Dr. Wurtman said, to compare brain samples obtained after equivalent numbers of hours following death.

Dr. Nitsch found that the membrane levels in brain cells are deficient, while the levels of membrane breakdown products are very high. Moreover, brain levels of choline and those of a closely related compound, ethanolamine, were reduced by almost half.

The main uses of choline and ethanolamine in normal brains are in the production of membranes, both those that provide cell boundaries and those within neurons (for example, the membranes surrounding the cell's nucleus). For this purpose, the choline and ethanolamine are incorporated within larger molecules, called phosphatides-specifically phosphatidylcholine (also known as "lecithin") and phosphatidylethanolamine. These phosphatides are continuously being synthesized and broken down as the neurons "remodel" their membranes.

In Alzheimer's disease brains, levels of phosphatidylcholine and phosphatidylethanolamine per nerve cell were significantly reduced, while those of their breakdown products, called GPC and GPE, were doubled. The exact causes of these abnormalities are unknown.

The researchers speculate, based on these findings, about why certain brain cells-those which produce acetylcholine-seem to be particularly vulnerable in Alzheimer's Disease. They note that acetylcholine is also produced from choline, so when choline is in short supply, less acetylcholine is made, probably causing a signal to be generated which leads more choline to be taken from its "reservoir" in membranes, and used to make additional acetylcholine. The lack of acetylcholine leads to some of the symptoms of the disease-the impaired memory and learning-while the accelerated breakdown of membranes in the acetylcholine-secreting nerve cells makes these cells highly vulnerable, and can lead to their death.

The new findings suggest, Dr. Wurtman commented in an interview, that if new drugs are to be developed to treat patients with Alzheimer's disease and to slow or stop the death of acetylcholine-releasing nerve cells, it's important that these drugs not further contribute to the "auto-cannibalism" process whereby the cells break down their membranes faster to liberate choline to make acetylcholine.

"The reason that we looked in human brains in the first place," he said, "was because the theory of "auto-cannibalism"-based on rat studies-predicted the changes in choline metabolism that we subsequently observed."

An ideal drug, he said, might be one which both increases the amounts of acetylcholine released from the cells, and at the same time raises choline levels, and thus protects the membranes from accelerated breakdown.

The other principal researchers involved in the collaborative study were John H. Growdon of the Department of Neurology at Massachusetts General Hospital, Jan K. Blusztajn of the Department of Pathology at the Boston University School of Medicine, and Anastassios Pittas and Barbara E. Slack of MIT.

A version of this
article appeared in the
March 4, 1992

issue of MIT Tech Talk (Volume
36, Number
22).


Topics: Neuroscience

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