Sci. Aging Knowl. Environ., 1 December 2004
Partners in Death
Alzheimer's protein rouses cell-suicide enzyme
Like a mob boss ordering a hit, a protein that mars the brains of Alzheimer's disease (AD) patients gets others to do its dirty work. The protein slays brain cells by activating a molecule that goads cells to kill themselves, according to new work. The findings add to evidence that the problem in AD arises within cells rather than outside of them.
Globs of amyloid accrue between cells in the brains of AD patients, and according to the standard view, these clumps kill neurons (see "Detangling Alzheimer's Disease"). But evidence that cell death is an inside job has been trickling in. Nine years ago, researchers genetically altered mice to manufacture A 42, a particularly deadly form of the protein, in their neurons. Amounts of p53, an enzyme that promotes cell suicide, rocketed in brain cells, and the animals developed amyloid buildup only after their neurons had begun dying. Two years ago, neuroscientist Andréa LeBlanc of McGill University in Montreal, Canada, and colleagues showed that injecting A 42 into human neurons killed the cells, but simultaneously thwarting p53 spared them. Neuroscientist Yasumasa Ohyagi of Kyushu University Hospital in Japan and colleagues wanted to explore the p53- amyloid connection.
To determine whether amyloid can activate the p53 gene, the researchers created DNA snippets identical to part of the gene's promoter, or on-off switch. In the test tube, A 42 glommed onto the pieces but not to promoters for two other genes. That finding suggests that the protein might flip on p53 production--if it can reach the cell's nucleus. Previous work revealed that reactive oxygen species (ROS) accumulate in AD patients' brains, and the researchers had discovered that dosing guinea pig neurons with the ROS hydrogen peroxide stimulated A 42 to accrue in cells. In fresh experiments, the investigators showed that the same abuse stimulated A 42 to accumulate inside the nucleus and boosted quantities of p53 within cells. They then examined brain cells from mice genetically altered to amass plaques. Compared with controls, the rodents carried more p53-encoding RNA. Moreover, deteriorating neurons in the rodents' brains held large quantities of A42 and p53. The researchers found a similar pattern in brains of AD patients. Overall, the results support the idea that amyloid slays cells from within and suggest that it kills by turning on p53, the researchers conclude. The findings are important for designing AD treatments because drugs that focus on cleaning up external amyloid might not stop the disease, Ohyagi says.
"The ability of amyloid to turn on [production] of p53 is exciting," says LeBlanc. The paper presents an intriguing hypothesis, says AD researcher Steven Younkin of the Mayo Clinic in Jacksonville, Florida. The next step is to show in animal models that breaking the link between amyloid and p53 saves neurons. A key issue, the researchers agree, is determining how amyloid gets into the cytoplasm; cells usually keep it locked away inside organelles. That work might reveal whether amyloid makes p53 an offer it can't refuse.
December 1, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150