Removing an Enzyme Inhibitor Protects Against Alzheimer's Disease

Armed with the prior knowledge that the enzyme cathepsin B normally breaks down amyloid proteins, they sought ways to make it function more effectively.

Results published in the October 23, 2008, issue of the journal Neuron revealed that the action of cathepsin B is regulated by the protease inhibitor cystatin C. Using genetic engineering techniques to reduce the levels of cystatin C in the brains of AD mice, the investigators were able to increase cathepsin B activity and lower the concentration of plaques and plaque precursors. Furthermore, the removal of cystatin C weakened the animals' plaque-associated cognitive deficits and behavioral abnormalities.

"Our strategy to harness the activity of a powerful plaque-degrading enzyme takes advantage of the brain's own defense system to remove the toxic build-up,” said senior author Dr. Li Gan. "In principle, one could boost the activity of cathepsin B by expressing more of it in the brain or by reducing the activity of cystatin C, its natural inhibitor. We focused on the latter strategy because it has greater long-term therapeutic potential. Our results suggest that cystatin C reduction has major therapeutic potential, and the next step will be to develop pharmacological approaches to inhibit cystatin C in the human brain.”

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