Molecular evildoers team up to launch neural destruction
NEW ORLEANS — The smoking gun for Alzheimer’s disease was discovered years ago, but new research has closed in on who pulls the trigger.
Brains of people with Alzheimer’s disease are riddled with plaques. Those plaques are made up of fibers composed of a protein fragment known as amyloid-beta, or A-beta. Tangles of another protein called tau snarl inside nerve cells of the patients’ brains. Plaques and tangles are signs that neurons have been murdered. Most researchers agree it’s the soluble forms of A-beta and tau that actually stage the killing, but they don’t agree on which molecule is the triggerman.
The debate has remained unsettled largely because researchers have mostly focused on how the plaques and tangles form, and that’s too late in the disease, contends George Bloom, a cell biologist and neuroscientist at the University of Virginia in Charlottesville. By then, diseased brain cells are all but wearing toe tags.
Bloom and his colleagues set out to study the earliest steps in the disease, paying special attention to what A-beta and tau do that leads to neuron death. The molecules may cause destruction by badly shaking up the status quo in the brain.
A twisted version of A-beta makes tau go rogue and persuade established brain cells to start dividing again, Bloom and his colleagues reported in March in the Journal of Cell Science. Bloom speculates that attempts at cell division may spell the end for neurons because they essentially rip themselves apart when they try to split into new cells.
One toxic variety of amyloid-beta bands together in small clumps called oligomers. These small gangs of A-beta then spur proteins called kinases to decorate tau with phosphate molecules, which change that protein’s function, Bloom’s team found. This corrupted version of tau is necessary for neurons to attempt cell division.
Now Bloom and his colleagues have found other players in this ring of corruption. Among proteins implicated in initiating Alzheimer’s disease is a master regulator known as mTOR, he reported December 15 at the annual meeting of the American Society for Cell Biology. The protein has long been known to govern how cells respond to nutrients and starvation, to regulate the recycling of cell components and to control cell growth, metabolism and proliferation.
In the new work, Bloom’s team found that tau and mTOR regulate each other’s behavior. Their constant checks on each other keep neurons from attempting to divide. But A-beta oligomers somehow throw mTOR off balance, leading to the defacing of tau. Without mTOR’s help, even bad boy A-beta can’t push tau off the straight and narrow. Once tau has gone bad it no longer needs encouragement from A-beta to wreak havoc, but it still needs mTOR. In other words, the three molecules work hand-in-hand to initiate the disease process.
Debate is sure to be waged over the details of Bloom’s idea, says Erika Holzbaur, a cell biologist at the University of Pennsylvania in Philadelphia. But “at the very least it’s a creative new way of looking at it.” If Bloom is right and mTOR is involved in the disease’s onset, the finding could be relevant to understanding other neurodegenerative diseases, she says.
A. Norambuena et al. Ectopic cell cycle re-entry, a major cause of neuron death in Alzheimer’s disease is controlled by Rac1 and mTOR. American Society for Cell Biology Annual Meeting, New Orleans, December 15, 2013.
M.E. Seward et al. Amyloid-β signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer’s disease. Journal of Cell Science. Vol. 126, March 1, 2013, p. 1278. doi: 10.1242/jcs.1125880.
L. Sanders. Memories Can’t Wait. Science News Vol. 179, March 12, 2011, p. 24.
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