Trojan-horse therapy blocks buildup of Alzheime...( A new therapeutic approach to Alzheimer...)

A new therapeutic approach to Alzheimer's disease protects brain cells in culture by drastically reducing the neurotoxic amyloid protein aggregates that are critical to the development of the disease. The treatment involves dispatching a small molecule into the cell to enlist the aid of a larger "chaperone" protein to block the accumulation of the brain-clogging protein.

The new "Trojan horse" technique overcomes a major challenge in drug design namely, the limited ability of molecules small enough to enter a cell to interfere with interactions between much larger proteins. The researchers said it might also be possible to use this new approach to sabotage proteins central to pathogenic organisms, such as human immunodeficiency virus (HIV).

Led by Howard Hughes Medical Institute investigator Gerald R. Crabtree, the researchers reported their findings in the October 29, 2004, issue of the journal Science. First author Jason Gestwicki and senior author Isabella Graef are both members of Crabtree's laboratory at Stanford University School of Medicine.

The plaques that clog the brains of people with Alzheimer's disease develop through the buildup of amyloid protein chains from individual units called A peptide. "There have been many attempts by pharmaceutical companies to develop A peptide inhibitors -- mainly by screening for small molecules that would bind to those aggregates and hoping that they would prevent further aggregation," said Crabtree. "But instead, what happens in virtually all cases is that those molecules just fit right into the aggregates and don't prevent aggregation at workable concentrations."

The issue, he explained, applies not just to amyloid aggregation, but also to protein interactions in general. "The insurmountable problem has been that protein interactions represent the binding of two large, perfectly matched surfaces," said Crabtree
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
28-Oct-2004

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