Hints of a brain toxin in Alzheimer's.

Hints of a Brain Toxin in Alzheimer's

Scientists have found the first evidence that protein deposits in the brains of people with Alzheimer's disease may contain a compound toxic to nerve cells. It remains unclear whether their experiments, performed on cultured cells, reflect the situation in living brain tissue. Nonetheless, the findings offer tantalizing new clues abot Alzheimer's potential underpinnings, supporting the hypothesis that a glitch in the biochemical processing of a normal brain protein causes the debilitating, neurological disease.

Despite a decade of research, the cause of Alzheimer's continues to elude scientists. In particular, researchers are vexed by their inability to determine whether the protein-rich deposits, or plaques, seen in Alzheimer-afflicted brains are a cause or a by-product of the disease. Plaque formation is accompanied by brain cell death, progressive memory loss and dementia.

Rachael L. Neve of the Harvard Medical School in Boston Knew that amyloid-a protein present in relatively small quantities in normal brains -- is the major componenet of Alzheimer's plaques, and that each piece of amylod is a fragment of a much larger protein common in n ormal brain tissue. She and her colleagues genetically engineered cells to mass-produce amylod, and found it had no effect on healthy neurons in culture. But with a little more genetic tinkering, the researchers reprogrammed their cells to secrete a slightly longer protein fragment -- one made of the amyloid segment and 63 additional amino acids that normally adjoin it within the large, precursor protein. The new protein proved deadly to cultured ner cells.

"We want to be very cautious about saying that this piece is involved in Alzheimer's disease," says Neve. Scientists so far have found only indirect evidence of her augmented amyloid in the brains of Alzheimer's patients. However, other experiments indicate that normal brain enzymes could easily cut her fragment from the amyloid precursor protein. Neve says the toxic fragment's structure suggests that in most people it would remain safely embedded in a nerve cell membrane, rendering it harmless. But in Alzheimer's patients, a cellular defect might allow its release. "It's possible that this [neurotoxic piece] could be generated first and then get further broken down to produce what's in the plaques," she says.

Other researchers agree that Neve's work, described in the July 28 SCIENCE, is the first to associate any neurotoxic effects with an amyloid-related protein. But it has yet to be reconciled with findings published in the March 17 SCIENCE by University of California, Irvine, researcher Carl W. Cotman and colleagues. They chemically synthesized a closely related amyloid fragment that temporarily enhanced nerve growth.

"The story is going to be fairly complicated, and there may be a variety of different functions served by these different fragments of the larger molecule," Cotman says. Nonetheless, he adds, Neve's use of living cells to produce her fragment is "a lovely methodological approach" that will prove useful as scientists seek to create and test other potentially significant Alzheimer's proteins.

If ongoing experiments confirm a role for Neve's protein in Alzheimer's, further research could lead to the development of drugs capable of blocking its effects, she says.