Biomedical Engineering Reference
In-Depth Information
levels of APP substrate, but data suggest that BACE1 has lesser effects on
normal physiological levels of APP for Ab production.
The important question to answer is: what protease target can be inhibited
under conditions of normal APP levels to reduce Ab? This question is
addressed by results showing that inhibition of cathepsin B by CA074Me
reduces brain Ab in brains of normal wild-type guinea pigs.
44,51
These data
indicate that cathepsin B functions at normal levels of APP for Ab production.
Despite the fact that BACE1 was discovered as a b-secretase more than a
decade ago, combined with the expenditure of extraordinary resources and
effort to develop BACE1 inhibitors, no BACE1 inhibitor is known to be
clinically effective to reduce brain Ab in patients. There is clearly a critical need
for exploration of multiple AD therapeutic agents. The inhibitors of cathepsin
B are effective Ab-lowering agents that result in improved memory in AD
mouse models. It is, thus, essential to develop such inhibitors of cathepsin B as
candidate therapeutic agents for AD patients.
6.6 Cathepsin B Inhibitors as Potential Therapeutic
Agents for the Majority of AD Patients Expressing
Wild-Type APP
Results indicate cathepsin B as a valid target for therapeutic reduction in brain
Ab, as indicated by the data showing that inhibitors of cathepsin B result in
effective improvement in memory deficit and reduction in brain Ab in mice
expressing human APP with the WT b-secretase site. The differences in drug
response in AD mouse models with the WT or Swe mutant b-secretase site
indicate the importance of genetic features for drug ecacy. Notably, because
the majority of AD patients express WT APP, and cathepsin B has specificity
for the WT b-secretase site, cathepsin B is a valid drug target for AD. These
findings suggest that development of cathepsin B inhibitors may be useful for
novel therapeutic strategies in AD.
Acknowledgments
This research was supported by the NIA/NIH R21 Grant AG027446 and
1R44AG032784 (to American Life Science Pharmaceuticals (ALSP)). V.H.
holds equity in ALSP and serves on the Scientific Advisory Board of ALSP.
The terms of this agreement have been reviewed by the University of Cali-
fornia, San Diego, in accordance with its conflict of interest policies. G.H.
holds equity in and is employed by ALSP.
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