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Researches Find clues to Cause of Alzheimer's

By Karen Kaplan
Executive Editor

MIT researchers studying Alzheimer's disease are slowly unearthing clues that might lead to a cure.

Alzheimer's is a degenerative neurological disease that results in progressive memory loss. Patients often forget how to speak, become unable to recognize close family members, and eventually are reduced to mental vegetables over an eight-year period, although their bodies may remain completely healthy, said Roger M. Nitsch, a postdoctoral fellow in the brain and cognitive sciences department.

Although no one knows the cause of Alzheimer's disease, researchers are making progress in describing the symptoms and the way in which the disease develops.

About 10 percent of all cases of Alzheimer's are labeled "familial," and thought to be genetically inherited. A point mutation in an amyloid precursor protein (APP) gene is thought to cause the disease in a handful of families, Nitsch said.

Strings of proteins weave through cell membranes in neural cells, crossing the extracellular wall at a section known as B/A4. Usually, protein strings are severed in the B/A4 region outside the cell membrane. But in Alzheimer's patients, the protein is cut abnormally -- twice on the boundaries of the B/A4 region. Once the B/A4 section is loose, it multiplies, forming an amyloid plaque, a self-aggregating accumulation of chemically inert abnormal peptides, or chains of proteins. The plaques accumulate in the extracellular regions of the brain, and although researchers do not understand how the amyloid plaques lead to Alzheimer's, they are one of the hallmarks of the disease.

Three lines of research

Nitsch and other researchers pursue three lines of research: One involves acetylcholine, a neurotransmitter critical to memory. Scientists have shown that when animals are taught to perform certain tricks and later suffer a lack of acetylcholine, they are often unable to repeat the tricks. Animals lacking the neurotransmitter are unable to learn the trick in the first place.

Nitsch and his fellow researchers examined whether acetylcholine acts to stimulate normal cleavage of APP, and therefore whether a lack of the neurotransmitter leads to less normal cleavage and more abnormal cleavage. They hypothesized that Alzheimer's patients have less of the critical neurotransmitter in their brains, resulting in fewer instances of normal cleavage of the acetyl precursor protein. This would result is more abnormal cleavage, where the B/A4 region is separated out and forms the deadly plaques.

The researchers found that acetylcholine levels are lower in the brains of Alzheimer's patients. Indeed, they found that several neurotransmitters occurred in lower levels in Alzheimer's brains compared to the brains of healthy people. "This is especially interesting because there's a major decrease in acetylcholine, but all other [neurotransmitters] are decreased as well," though to a lesser extent, Nitsch said. "Acetylcholine is necessary for correct cleavage [of APP], and when you have less of it, that opens the way for a higher incidence of the abnormal cleavage that characterizes Alzheimer's," Nitsch said.

Another line of research also concentrates on the cutting of the protein near the cell membrane. Here, researchers concentrated on how the B/A4 region is cut from the rest of the protein string. One of the cuts on one side of the region occurs inside the wall of the cell membrane. "Usually you don't have cleavage within a membrane, so we hypothesized that there must be a membrane defect in Alzheimer's patients," Nitsch explained.

The researchers studied membrane metabolites, major structural molecules that make up membranes in cells, from the brains of Alzheimer's patients and compared them with membrane metabolites from healthy people and from people who suffer from other neurological diseases, such as Huntington's disease, Parkinson's disease, and Down's syndrome. They found that "levels of major phospholipids were depleted in Alzheimer's brains," and that there were twice as many breakdown products in Alzheimer's brains compared to the other brains, Nitsch said. This suggests "an accelerated breakdown of cell membranes in the brains of Alzheimer's patients," he said.

The third research project involved measuring levels of choline, a precursor of acetylcholine and the important membrane component phosphacetylcholine, in Alzheimer's brains. Choline is a nutrient that can be found in some foods, including eggs. Measured choline levels were lower in Alzheimer's brains compared to healthy people and patients with other neurological diseases, "but it's unclear why choline levels are decreasing," Nitsch said.

The results of the membrane defect research and the choline deficiency research were published last month in The Proceedings of the National Academy of Sciences. Other research results were submitted for publication two weeks ago, Nitsch said.

Direction for future research

Nitsch will now focus his attention on "how molecular and cellular mechanisms are responsible for abnormal cleavage" of APP. "We hope that as a result we'll understand the mechanism that leads to abnormal APP processing and that we can find a drug to interfere with the abnormal cleavage process or stimulate the normal cleavage process," he said.

Another avenue to consider is why Alzheimer's develops abnormalities only in the brain, since APP is present throughout one's body. "We suspect that neurons have a selective vulnerability" to the abnormal cleavage process, "but we don't know for sure," he said. "Perhaps we can learn from other cells how to avoid this damage, and teach neurons to learn the processes of other cells by treating them with a drug."