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Biological Chemistry

Membrane Anchors May Outwit Alzheimer's

April 28, 2008 | A version of this story appeared in Volume 86, Issue 17

Cell-membrane-spanning protease enzymes called β-secretases play a critical role in β-amyloid peptide formation, a key step in the progression of Alzheimer's disease. Although several small-molecule inhibitors are capable of shutting down β-secretase's activity, many of them are inactive on intact cells, limiting their potential as Alzheimer's therapies. A multi-institution team led by Kai Simons of the Max Planck Institute of Molecular Cell Biology & Genetics in Dresden, Germany, has now shown that affixing such an inhibitor to the plasma membrane makes it more effective at stopping β-secretase (Science 2008, 320, 520). The researchers linked a peptide that inhibits β-secretase to a sterol, which targets the inhibitor to cholesterol-rich "lipid raft" sections of the membrane. In cell cultures, the new inhibitor effectively reached endosomes, the membrane-bound compartments inside cells where most β-secretase activity takes place. The inhibitor also reduced β-amyloid production in a mouse model of Alzheimer's. The anchoring approach may prove useful for targeting other disease-causing membrane proteins as well, the authors write. Simons is a founder of Jado Technologies, a Dresden-based company that is focusing on cell-membrane chemistry involving lipid rafts to address Alzheimer's and other diseases.


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