NEW YORK (Reuters Health) - By linking an amyloid ligand to a large “chaperone” protein, researchers may have hit upon a strategy to prevent the toxic aggregation of beta-amyloid into fibrils that characterize Alzheimer’s disease.
Previous studies have had little success in using low-molecular-weight drugs to inhibit amyloid-beta aggregation.
“To approach this problem,” Dr. Isabella A. Graef and colleagues write in the October 29th issue of Science, “we envisioned a Trojan horse strategy in which a small bifunctional molecule would gain access to the relevant biologic compartment, bind tightly to a chaperone, and thereby gain the steric bulk needed to disrupt a protein-protein interaction.”
The pathologists, from Stanford University Medical School in California, synthesized a molecule composed of the amyloid ligand Congo red (CR) covalently bound to SLF -- a synthetic ligand for the large FK506 binding protein (FKBP).
Individually, CR, SLF-CR and CR/FKBP had little or no effect when combined with beta amyloid. However, SKF-CR bound to FKBP at concentrations as low as 10 micromolar almost fully blocked fibril formation, although beta amyloid was still able to form small aggregates.
Cultured hippocampal neurons treated with amyloid beta exhibited increased cell death and abnormal cell morphology, with neurites becoming dystrophic and showing signs of nuclear fragmentation and membrane blebbing.
However, neurotoxicity was significantly reduced by the addition of SKF-CR/FKBP, with neurons displaying fairly normal morphology.
Dr. Graef’s team generated even more potent inhibitors by altering the linker between SKF and CR, some of which were capable at nanomolar concentrations of preventing amyloid beta neurotoxicity. But in each case, the potency of the compounds relied on the availability of FKBP.
“Directly inhibiting amyloid beta aggregation with the recruited-chaperone approach might provide a viable complement to recent efforts to reduce the rate of amyloid beta release, enhance its clearance, or template nontoxic aggregates,” they conclude.
However, it will be some time before this technology has clinical application, since Congo red does not enter cells or cross the blood-brain barrier, Dr. Peter Lansbury, a chemist at Harvard Medical School in Boston comments in a Science news release.
Source: Science 2004;306:865-869. [ Google search on this article ]
MeSH Headings:Amyloid: Neurofibrils: Drugs, Investigational: Amyloid beta-Protein: Neurofibrillary Tangles: Cell CultureCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
