Sometimes one plus one adds up to more than two.
When a team of Johns Hopkins researchers brought together two genes implicated in the development of Alzheimer's disease, they found that the paired genes brought on the brain-clogging plaques that characterize the disease more rapidly than either gene alone.
The two sets of genes were housed in the brains of specially bred mice. One gene, called APP, for amyloid-precursor protein, produces the amyloid plaques in the brains of human Alzheimer's victims.
"The mice with APP genes are at the threshold of developing plaques," said David Borchelt, an associate professor of pathology who has been collaborating with Donald Price, Sangram Sisodia and Michael Lee. "They produce plaques only at the end of their normal lifespans."
A mutated form of the other gene, Presenilin 1, is known to develop a lot of plaques in the kind of Alzheimer's disease that runs in families and often begins much earlier in life than the non-inherited type.
Borchelt's team set out to answer two questions. First, they wanted to see what the mutant Presenilin 1 protein did by itself. Alone, there were no changes in the brain cells.
"Nothing we could see was obviously wrong with the mice," he said. "The cells in their nervous systems were normal."
Next, they wanted to see if the Presenilin 1 protein would have an effect on the action of the APP gene. Indeed, they concluded, the two genes did work in the same genetic pathways-- although exactly how isn't yet clear.
More important, the combination of these two genes sharply accelerated the formation of plaques. The presence of the mutated Presenilin 1 seemed to increase the brain levels of amyloid-beta peptide, the protein that clumps to form the plaques. The increase was only slight but made an enormous difference in how soon the plaques formed. They began appearing in half the time-- after nine or 10 months instead of 18-20 months with the APP gene alone.
Previously, scientists believed that the plaques were the end product of the disease. But the work of Borchelt's team now throws that assumption into question. In human disease, it is hard to know what comes first. The plaques are always there, but so are other lesions.
Other research directions were interesting but inconclusive, said Borchelt. People with Down syndrome, for instance, develop much of the brain pathology of Alzheimer's disease, showing some evidence that plaques form early. But the genetic background of these individuals is so different from that of most Alzheimer's sufferers that their experience may not be a valid guide.
"This new research suggests that the amyloid plaques are a necessary and crucial event in the development of Alzheimer's disease," said Borchelt. "The earlier this process begins, the earlier Alzheimer's begins."
The doubling of the speed at which the plaques appear under the influence of the two genes may have eventual implications for treating Alzheimer's disease.
If, reasons Borchelt ("and it's a big if," he said), doubling the amount of amyloid-beta peptide that produces the plaques speeds up the process, then--perhaps--halving the amount of this peptide would push the onset of Alzheimer's disease beyond the normal human lifespan.
"Now, Alzheimer's disease usually begins between ages 65 and 85," Borchelt said. "If we could develop a compound which would cut the amount of the peptide produced by a factor of only two, we could stop Alzheimer's."
Such drug research is only now beginning and testing is at least five years away, he said.
The team's research was supported by funding from the Develbess Fund, the Adler Foundation, the National Institute of Aging and the National Institutes of Health.
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