Does your brain shutdown with Alzheimer's?

June 12, 2002

FOR people with Alzheimer's disease, memories seem to leak away like the charge draining from a dying battery. The image is an apt one, because experiments on nerve cells suggest that as Alzheimer's takes hold, electrical charge may leak out of the brain cells, forcing them to "power down" and die, taking cherished memories with them.

The finding points to a new and unexpected mechanism for the way Alzheimer's disease damages the brain. And while the effect has yet to be demonstrated in living animals, there is tantalising evidence that drugs which block the effect could one day lead to new therapies for the condition.

Alzheimer's patients develop plaques in their brains when protein fragments called beta-amyloid clump together. When these plaques touch healthy brain cells, channels on the cell surface open up to let in a flood of calcium ions. This upsets the chemical balance of the cell, and it dies.

But it now turns out that another damaging process takes place that might help to kill off the cells. According to Vernon Ingram and a team at the Massachusetts Institute of Technology, the plaques appear to promote an additional flood of ions that destroys the potential difference that exists between the inside and the outside of a cell.

"Normal cells are negatively charged inside and positively charged on the outside," says Ingram. This potential difference across the cell membrane allows it to receive electrical signals from neighbouring cells. But Ingram's team found that when a plaque touches the cells, as well as positive calcium ions flooding in, negative chloride ions flow out, quickly draining the cell of its negative charge, just like a battery going dead.

Ingram, Barbara Blanchard and Veena Thomas added a special dye to cultures of human and rat nerve cells. The dye allows the researchers to measure the flow of ions, and hence the potential difference, across cell membranes. When they then added the amyloid peptide, the effect was dramatic: the cells became depolarised within minutes. "If this happens in memory-forming cells, you lose your memory," says Ingram.

Next, they exposed the depolarised cells to 1500 known drugs. The dye showed that 10 of the drugs reversed the depolarisation, restoring cells to normal. Some of these drugs are known to block channels that allow chloride ions to leave the cell, so an outward flow of chloride ions must be helping to depolarise the cell. Others blocked protein kinase C, an enzyme which may orchestrate the depolarisation from within the cell. The team now wants to test the drugs on brain slices from mice, and on live mice engineered to develop similar symptoms to Alzheimer's.

Richard Harvey, director of research at the Alzheimer's Society in London, is not convinced Ingram's group has hit on the key to Alzheimer's. "There's no evidence that membrane depolarisation is the most critical disease process," he says. "But I might be wrong." Neil Buckholtz, director of the dementias branch of the National Institute on Ageing in the US, says we need to know whether the drugs can actually cross the blood-brain barrier before any clinical trials.

Ingram agrees there's more to be done. "So far, we've only shown this in cell cultures," he says. "But it's a very promising first step and we're very excited about this."
Author: Andy Coghlan

More at: Biochemical and Biophysical Research Communications (vol 293, p 1197 and p 1204)

New Scientist issue: 15 JUNE 2002


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