Take Two: Rival Alzheimer's proteins unexpectedly collaborate to kill cells (Neurodegenerative disease)

Abstract

New research might reconcile scientists who have been battling over what launches Alzheimer's disease (AD). Most neuroscientists fall into one of two warring camps, each of which blames a different renegade protein. Now, tests in cultured neurons show that the proteins collude to eradicate neurons. The results also suggest an unexpected therapy for the neurodegenerative disorder. In Alzheimer's-wracked brains, abnormal protein plaques surround dying nerve cells that are packed with tangles made from a different protein. One group of researchers argues that the predominant protein in the plaques, β amyloid, instigates deterioration. Its opponents counter that tau, which fills neurons with protein tangles, might choke brain cells to death (see "Detangling Alzheimer's Disease" ). Recent evidence has suggested that β amyloid targets tau to stir up trouble. Sprinkling this plaque-forming protein onto neurons growing in culture kills cells, perhaps by inhibiting tau's ability to stabilize microtubules, long protein beams that reinforce the neuron's spindly projections. To further probe this issue, Rapoport and colleagues tested whether β amyloid needs tau to do its dirty work. Neurons from mice that make tau start shriveling and dying within 6 hours of being dosed with β-amyloid protein. When the researchers dropped a pinch of β amyloid onto neurons that lack tau, however, the cells churned along for 4 days. These results indicate that tau is required for β amyloid to kill the cell. The team also examined the cells' microtubules. These protein strands must grow and shrink constantly to perform their cellular jobs properly. In cells lacking tau, microtubules expanded and contracted more readily than did those found in normal neurons. The researchers suspected that this agility might be key to β-amyloid resistance, so they repeated their experiments with taxol, a cancer-fighting chemical that, like tau, prevents the protein rods from disassembling. In the presence of taxol, β amyloid killed the cultured neurons, regardless of whether the cells sheltered tau. Taxol alone did no harm. Taken together, the results suggest that a microtubule-stabilizing agent is required for β amyloid to destroy cells and hint that the two Alzheimer's proteins--tau and β amyloid--collaborate to cause neurodegeneration. The paper makes a "wonderful contribution" to understanding the relation between the two proteins, says neurologist Kenneth Kosik of Harvard Medical School in Boston. However, he questions how accurately cell culture behavior mimics events in an animal. For example, "no one has seen tangles in cultures," says Kosik, so the cultured neurons don't fully emulate the diseased brain. Still, the new findings might inspire scientists to pursue a new therapeutic avenue, says Michael Hutton of the Mayo Clinic in Jacksonville, Florida. If the results transfer to animals, he says, destabilizing microtubules could prove therapeutic--an outcome that might bring a cease-fire to AD research and peace to many people. --Mary Beckman M. Rapoport, H. N. Dawson, L. I. Binder, M. P. Vitek, A. Ferreira, Tau is essential to β-amyloid-induced neurotoxicity. Proc. Natl. Acad. Sci., 16 April 2002 [e-pub ahead of print]. [Abstract] [Full Text]