By Lisa Seachrist

Washington Editor

Fading memories and progressively erratic moods characterize the dementia that physicians associate with Alzheimer's disease, but the definitive diagnosis comes only when the hallmark deposits of amyloid protein in the brain are discovered after death.

As much as these deposits or plaques serve as harbingers of Alzheimer's disease, researchers have hotly debated whether the plaques represent the means by which Alzheimer's takes its toll or are simply a by-product of the disease itself. Recent discoveries involving two genes associated with familial cases of early onset Alzheimer's implicate increased levels of amyloid production as a likely cause of the disease.

New results from Martin Cistron and Dennis Selkoe, of Harvard Medical School published in the January Nature Medicine add further weight to the idea that one of the principle problems in Alzheimer's disease is an increased amount of amyloid that's likely to form plaques. The paper is titled "Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid ß-protein in both transfected cells and transgenic mice.

"The bottom line is that our work adds support to the amyloid hypothesis," said Martin Cistron, assistant professor of neurology at Harvard Medical School. "Our work suggests that the increase in amyloid production comes early in the disease process."

Since 1987, researchers have known that ß-amyloid (Aß) is the primary component of Alzheimer's disease plaques. The protein gets cleaved in primarily two forms: a 40-amino acid protein and a 42-amino acid version. It is the 42 amino acid version of Aß that appears most likely to seed plaque deposits in the brain. Mutations in the gene that encodes Aß can cause some early forms of familial Alzheimer's disease.

New Plaques Discovered In 1996

In 1995, back-to-back discoveries of two proteins presenilin 1 and presenilin 2 (PS-1 and PS-2) added two new players in Alzheimer's. Nearly half of all inherited forms of Alzheimer's result from mutations in PS-1 or PS-2.

Earlier this year, Steve Younkin of the Mayo Clinic in Jacksonville, Fla., reported that the fibroblast cells cultured from the skin of patients with defects in the presenilin genes produced more Aß 42 than people who lacked the mutations. And, Younkin and colleagues also found that Alzheimer's disease patients with presenilin mutations had higher levels of Aß 42 circulating in their bloodstreams than those who didn't harbor the mutations.

Cistron, Selkoe and colleagues tested whether introducing mutant PS-1 and PS-2 genes into laboratory cell lines would increase the amount of Aß 42 the cells produced. The mutant genes caused a significant increase in the amyloid production whereas introducing normal presenilin genes had no effect.

The researchers also examined Aß 42 production in transgenic mice. The animals that had the mutant genes showed significant increases in Aß 42 as compared to the animals which had received the normal genes.

"Aß 42 production goes up in response to the specific mutations in the presenilin genes," Cistron said. "But, we still don't know what the mechanism for this response is. That is the next step."

Rudy Tanzi, director of the department of genetics and aging at Massachusetts General Hospital and Harvard Medical School in Boston called the work "an important affirmation."

"An increased ratio of Aß 42 to Aß 40 has evolved as the common denominator in Alzheimer's disease," Tanzi said. "Selkoe's work has reaffirmed that mutations in the presenilins increase that ratio. A small increase in Aß 42 may be enough to get a large amount of amyloid deposition over time."

Tanzi noted that while it seems obvious that the presenilins increase the amount of Aß 42 produced, it is unclear how these membrane-bound proteins * which are found primarily in the endoplasmic reticulum (ER) or in the golgi apparatus * cause such an increase. However, he has a favorite speculation.

The golgi and ER are primarily responsible for producing proteins that are correctly folded and functional. Tanzi suggests that the presenilins may actually edit out improperly folded Aß. "Mutations in the presenilins may prevent them from participating in the normal quality control allowing more Aß 42 to be produced," he said.

Even if the presenilins have nothing to do with protein quality control, Tanzi noted that "the next big step in Alzheimer's research will be to discover how the presenilins cause increases in Aß 42." *