Cathepsin B Cited Potential Alzheimer's Disease Drug Target

The cysteine protease inhibitor, E64d, reduces the amount of brain amyloid-beta protein and improves memory loss in Alzheimer's disease animal models by inhibiting cathepsin B, but not BACE1, beta-secretase activity.

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.

The protective role of cathepsin B has been called into question by results of a recent study published in the June 2011 online edition of the Journal of Alzheimer's Disease. In this study investigators at the University of California, San Diego (USA) administered a cysteine protease inhibitor, E64d, to normal guinea pigs or transgenic mice expressing human AbPP (amyloid-beta protein precursor), both of which express the human wild-type beta-secretase site sequence.

In the guinea pig model, oral E64d administration caused a dose-dependent reduction of up to 92% in brain CSF (cerebrospinal fluid), and plasma of amyloid-beta fragments. There was a reduction of up to 50% in the C-terminal beta-secretase fragment (CTFb), and a 91% reduction in brain cathepsin B activity, but increased brain BACE1 activity by 20%. In transgenic AD mice, oral E64d administration improved memory loss and reduced brain amyloid-beta fragments, amyloid plaque, brain CTFb, and brain cathepsin B activity, but increased brain BACE1 activity.

The results showed that oral administration of the cysteine protease inhibitor, E64d, not only reduced the build-up of beta-amyloid in the brains of animal models for Alzheimer's disease, but also resulted in a substantial improvement in memory.

"The finding is especially exciting because E64d has previously been shown safe for use in humans, so we believe the compound has strong potential as a new therapy for Alzheimer's disease," said contributing author Dr. Vivian Hook, professor of neurosciences, pharmacology, and medicine at the University of California, San Diego. "The study indicates cathepsin B as a new target for therapeutic inhibition of amyloid-beta production and subsequent improved memory function. This is an important finding because we show that beta-secretase inhibition can occur with cathepsin B inhibition and without BACE1 inhibition."

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