Sci. Aging Knowl. Environ., 6 February 2002
Inside Job: Alzheimer's protein kills neurons from within (Alzheimer's disease)
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/5/nw16
Key Words: amyloid A apoptosis p53 Bax Bcl2
Abstract: In the brains of people with Alzheimer's disease (AD), the spaces between neurons display one of the affliction's hallmark pathologies. There, senile plaques accumulate and perhaps trigger the decline in mental function that characterizes AD. But the protein that makes up these plaques can also kill neurons from the inside, according to new research. Considerable work needs to be done before the study's results can be extended from cell culture to humans, but the results hint that the dastardly protein could set AD in motion from within brain cells.
Clumps of the so-called -amyloid protein that build up amid damaged neurons are one of the defining characteristics of AD (see "Detangling Alzheimer's Disease" and Honig Case Study). These aggregations might kill neurons and lead to dementia, suggest some researchers, perhaps by instigating a destructive immune response or by initiating cell suicide mechanisms. But the nature of the link between plaques and AD hasn't been firmly established. Some studies suggest that amyloid accumulates within neuronal cells even before amyloid plaques appear outside, which led Zhang and colleagues to wonder whether amyloid might stir up trouble from the inside.
To find out, the group injected amyloid into neurons that had been removed from human brains and then measured their survival in culture. Neurons infused with a benign version of amyloid, called A40, or with control proteins sustained no ill effects. Cells that were shot up with the plaque-forming A42, however, suffered grievously: 1500 protein molecules per cell killed half the cells--and neurons in the brains of people with AD can harbor far more than 1500 A42 molecules, the authors estimate.
Additional experiments suggest that A42 inside the cell activates a well-studied cell death pathway. When the researchers delivered A42 together with molecules that block the function of a cell death-inducing protein called Bax, neurons no longer died at the hand of A42. A second protein, p53, that activates Bax is also implicated: Neurons that carry a mutation in p53 that obliterates its capacity to turn on Bax production similarly withstood the A42 assault. Together the results suggest that A42 kills cells from the inside by activating a cell death signaling pathway that includes p53 and Bax.
The experiments clearly show that A42 is toxic to cultured neurons, says neurologist David Holtzman of Washington University in St. Louis, Missouri. But the researchers injected A42 into the cytoplasm--the space inside a cell but outside the nucleus and other membrane-bound compartments--and Holtzman says he doubts whether A42 accumulates in the cytoplasm of neurons in the brain. Normally, cells manufacture and export A without exposing it to the cytoplasm. Structural biologist Peter Lansbury of Harvard Medical School in Boston suggests, however, that it might not take much cytoplasmic A42 to wreak havoc in the brain. "It's very possible that most of A ends up in extracellular plaques but that the stuff that's causing Alzheimer's disease is the 1% that doesn't," says Lansbury. Sometimes just a few well-placed individuals are all it takes to provoke disaster.
--R. John Davenport
Y. Zhang, R. McLaughlin, C. Goodyer, A. LeBlanc, Selective cytotoxicity of intracellular amyloid peptide1-42 through p53 and Bax in cultured primary human neurons. J. Cell Biol. 156, 519-529 (2002). [Abstract] [Full Text]
Citation: R. J. Davenport, Inside Job: Alzheimer's protein kills neurons from within (Alzheimer's disease). Science's SAGE KE (6 February 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/5/nw16
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