Sci. Aging Knowl. Environ., 27 April 2005
Alzheimer's protein kills by tampering with cell's antioxidant defenses
amyloid, the brain-clogging protein in Alzheimer's disease (AD), recruits other molecules to do its dirty work. It kills cells by enlisting certain proteins to sabotage oxidant defenses, a new study reveals. The work suggests that drugs that break the chain between amyloid and its henchmen might save neurons.
The brains of AD patients teem with lumps of amyloid (see "Detangling Alzheimer's Disease"). The protein can slay neurons by hiking the amounts of ruinous reactive oxygen species (ROS). However, researchers don't understand the molecular events that lead to the cell's demise. Neuroscientist Wanli Smith of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and colleagues suspected that the protein p66Shc, which governs cellular responses to ROS, might be involved. Mice lacking the protein live long and shrug off oxidative damage (see Martin and Friedman Perspective). Affixing a phosphate to p66Shc activates the molecule, stifling forkhead proteins, which goad cellular antioxidant defenses into action. Consequently, ROS-damaged cells die (see "Stay Mellow, Stay Young"). Smith's group wanted to determine whether amyloid rouses p66Shc and squelches forkhead proteins.
Bathing cultured cells with amyloid boosted the proportion of phosphate-studded p66Shc, the researchers found. Moreover, about four times as many cells perished after the treatment compared with those in amyloid-free cultures. amyloid also increased the amount of forkhead enzymes bearing phosphate, which prevents them from mobilizing ROS-fighting genes. The brain-scarring protein killed fewer cells when they were engineered to manufacture a phosphate-proof version of p66Shc, the researchers observed. These findings support the notion that amyloid activates p66Shc, which muffles forkhead proteins.
The researchers had previously shown that neurons die when amyloid activates a protein called JNK, which impedes a stress-fighting pathway under certain conditions. Cells with inactivated JNK sported much less phosphate-tagged p66Shc than did normal cells and were about half as likely to die after a dose of amyloid, they now find. Overall, the results suggest that amyloid murders cells by flipping on JNK, which in turn rouses p66Shc and squelches antioxidant defenses by shackling forkhead proteins. Because the death machinery requires JNK, the findings hint that drugs that block the protein might stem brain damage from AD, says Smith.
The study provides "definitive evidence for the involvement of JNK and p66Shc in the cell death" sparked by amyloid, says neuroscientist Mark Mattson of the National Institute on Aging in Baltimore, Maryland. Cell biologist Jeffrey Friedman of the Scripps Research Institute in La Jolla, California, calls the study "strong work." But he cautions that researchers need to confirm p66Shc's role in animal and human studies, because the protein might not be active in normal brain cells. Friedman also points out that in fruit flies, JNK activates forkhead proteins and pacifies ROS, contradicting the current findings (see "Feeling Spunky With JNK"). Flies lack p66Shc, which could explain the discrepancy, he says. In humans the protein might serve as a switch that determines whether JNK soothes or kills. Future work could reveal how to keep JNK from heeding amyloid's orders.
April 27, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150