Sci. Aging Knowl. Environ., 14 January 2004
Molecular hit man might help Alzheimer's protein take out brain's white matter
Alzheimer's disease (AD) decimates not only neurons, but also the white matter, the information-transmitting interior of the brain. A new study suggests that amyloid, the protein that accumulates in the brains of AD patients, incites this devastation by recruiting another molecule that provokes cell suicide. The results could help researchers craft ways to spare the brain in AD patients, although some experts are skeptical of the finding.
Researchers don't know why the white matter, which shunts signals from one part of the brain to another, deteriorates in AD. Two years ago, neuroscientists showed that amyloid massacres white matter cells called oligodendrocytes in the culture dish, but the mechanism is elusive. Circumstantial evidence links amyloid to ceramide, a molecule already incriminated in the neuron deaths of amyotrophic lateral sclerosis (see "A Greasy Way to Die"). Ceramide spurs cells to commit suicide and to stop dividing and settle into a state called senescence (see Obeid and Hannun Perspective). The amount of the molecule soars in the brains of AD patients. Ceramide and amyloid also elicit similar cellular damage, injuring mitochondria and exacerbating oxidative stress. These findings raise the possibility that amyloid kills white matter by stimulating production of ceramide, but no one had tested the idea.
To do so, neurologist Jin-Moo Lee of Washington University in St. Louis, Missouri, and colleagues gauged amyloid's effects on ceramide in oligodendrocytes. When the researchers doused cultured cells with amyloid, their ceramide concentrations shot up by 400%. The treatment also boosted amounts of one of the enzymes that makes ceramide. Blocking this enzyme or stifling its gene with a short strand of DNA cut the number of cell fatalities from amyloid in half. Together, those observations suggest that amyloid pumps up ceramide quantities by activating the enzyme, triggering cell death. The findings raise the possibility that amyloid is responsible for white matter loss and that the same mechanism kills other types of brain cells, Lee says. Although the researchers don't understand how amyloid rouses the enzyme, other work shows that it robs cells of glutathione, a chemical that sops up oxidants and inhibits the ceramide-making enzyme. amyloid might increase ceramide quantities by draining the cell's stocks of glutathione, which increases oxidative stress and activates the enzyme, the researchers hypothesize.
Previous studies only hinted at an association between ceramide and amyloid, says cell and molecular biologist Lina Obeid of the Medical University of South Carolina in Charleston. The new work "tightens the connection" by suggesting that amyloid influences the ceramide-making enzyme. Determining how they communicate might reveal ways to prevent AD's damage, she says. However, biochemist Elena Posse de Chaves of the University of Alberta in Edmonton, Canada, notes that inhibiting the enzyme or its gene did not reduce the enzyme's activity in the absence of amyloid, suggesting that these enzyme-hindering methods weren't working properly. Lee argues that in these situations, the tests might measure predominantly the activity of another enzyme form that doesn't respond to amyloid or the inhibitors. Researchers need further evidence before they can be sure they've caught the white matter killer.
January 14, 2004
Suggested by Patrick Kaminker.
Science of Aging Knowledge Environment. ISSN 1539-6150