Cathepsin B Inhibitors Ease Alzheimer's Symptoms by Blocking Amyloid Plaque Formation

Neurobiologists studying the molecular processes underlying Alzheimer's disease have identified the mechanism that explains how inhibition of cathepsin B activity blocks formation of the toxic amyloid-beta (Abeta) peptides that characterize the disease.

Cathepsin B was once suspected as being a protease participating in the conversion of beta-amyloid precursor protein into the amyloid plaques found in Alzheimer's disease patients. However, this function is now known to be mediated by BACE1 protease. It is now thought that cathepsin B can degrade beta-amyloid precursor protein into harmless fragments. Thus, it is conceivable cathepsin B may play a pivotal role in the natural defense against Alzheimer's disease.

However, new findings reported in the March 4, 2014, online edition of the Journal of Alzheimer’s Disease by investigators at the University of California, San Diego (USA) and colleagues at the biopharmaceutical company American Life Science Pharmaceuticals, Inc. (San Diego, CA, USA) have altered this concept by showing that cathepsin B gene knockout or its reduction by an enzyme inhibitor blocked creation of key neurotoxic amyloid-beta peptides linked to Alzheimer’s disease.

Using various mouse models, the investigators showed that oral administration of E64d a cysteine protease inhibitor of cathepsin B, not only reduced the build-up of beta-amyloid in the brains of these animals, but it also caused substantial improvement in memory.

“This is an exciting finding,” said senior author Dr. Vivian Hook, professor of pharmaceutical sciences at the University of California, San Diego. “It addresses a new target—cathepsin B—and an effective, safe small molecule, E64d, to reduce the pGlu-Abeta that initiates development of the disease’s neurotoxicity. No other work in the field has addressed protease inhibition for reducing pGlu-Abeta of Alzheimer's disease.”

Related Links:
University of California, San Diego
American Life Science Pharmaceuticals, Inc.