July 9, 2001 The molecule that spawns "plaque" buildup in the brains of Alzheimer's patients may also play a role in normal gene expression, suggests a study using cultured cells. The study will be published in the 6 July issue of the international journal, Science.
If these findings prove true in humans, they may help scientists understand why the plaques form and perhaps even the basic mechanisms that lead to the disease.
The study also raises the possibility of unwanted side effects from drugs intended to prevent plaque formation, by revealing a biological use for the reaction that produces the plaque molecules. Such drugs are currently under investigation as possible Alzheimer's therapies.
Researchers have long wondered about the normal function of the parent protein to the plaque molecules--the "amyloid precursor protein," or "APP," which is embedded in the cell membranes of neurons in the brain.
The protein is split into pieces by a series of enzymes. The last of these reactions, called "gamma cleavage," cuts the remaining molecule into two smaller pieces.
The infamous Alzheimer's plaques form from one of these pieces, the "beta-amyloid" peptide, which is secreted from the cell. The other piece is the APP "tail," which dangles from the membrane into the cell. Its function has thus far been a mystery.
In their Science study, authors Xinwei Cao and Thomas C. Südhof of the University of Texas Southwestern Medical Center and Howard Hughes Medical Institute propose that the APP tail enters the nucleus and participates in gene expression.
"This would, for the first time, provide a biological reason for gamma cleavage, which liberates beta amyloid fragment that causes Alzheimer's disease," said Südhof.
The researchers took their lead from another protein, called "Notch," which is found in the same part of the cell as APP and is cleaved by a related enzyme.
One of the Notch fragments then helps regulate a process called transcription, the copying of DNA into transportable RNA versions, which then direct protein assembly elsewhere in the cell. Südhof and Cao investigated whether the APP tail might do the same.
Transcription requires a complex assortment of molecular machinery to unzip the DNA double helix and assemble a corresponding RNA chain. Certain molecules must bind to the "start" section of the gene's DNA sequence, and help provide a hookup to the rest of the transcription machinery.
The Science authors found that the APP tail did help activate transcription, when it was bound with two other molecules. One, calledTip60, is part of a large complex of other transcription molecules. The other, Fe65 doesn't have a currently known function, but it may be part of the hookup mechanism that actually binds to the DNA, according to Südhof and Cao.
Because they didn't know which gene APP might bind to, the researchers borrowed velcro-like patches called binding domains from two other transcription molecules, known to activate genes that express fluorescent proteins.
Binding domains only provide the physical link to a certain gene; they don't activate transcription by themselves. The researchers fused one of the binding domains to the complex of the APP tail and its two partners, and then inserted the whole structure into a cultured tissue cell. Like a new light switch connected to an existing wiring system, the complex did activate the fluorescing gene.
"Transcription is an orchestra of factors that have to come together. We've shown that the APP tail can provide the hookup to the many other proteins needed for transcription," Südhof said.
One of the next important questions is which gene might be the APP tail's actual target. In the meantime, however, these findings may still shed light on mechanisms behind Alzheimer's, according to Südhof.
"The regulation of transcription would also, as a byproduct, regulate the amount of amyloid-beta produced. I think it is likely that Alzheimer's disease is in general a long term change in this regulation. What I'm hypothesizing is that, if this pathway is turned on more than normal over long periods of time, you'd produce more amyloid-beta;" said Südhof.
If this hypothesis turns out to be true, it would raise questions about the effectiveness of fighting Alzheimer's by preventing the splitting of APP.
"Indeed, if transcriptional regulation initiated by gamma-cleavage is an important function, which we have every reason to believe, gamma-secretase inhibitors may have as yet unexpected side effects, because they interfere with transcriptional regulation," Südhof said.
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