Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce beta-amyloid related to Alzheimer's disease.
Beta-amyloid (Abeta) in the brain is a major factor involved in Alzheimer's disease (AD) that results in severe memory deficit. Our recent studies demonstrate pharmacogenetic differences in the effects of inhibitors of cathepsin B to improve memory and reduce Abeta in different mouse models of AD. The inhibitors improve memory and reduce brain Abeta in mice expressing the wild-type (WT) beta-secretase site of human APP, expressed in most AD patients. However, these inhibitors have no effect in mice expressing the rare Swedish (Swe) mutant amyloid precursor protein (APP). Knockout of the cathepsin B decreased brain Abeta in mice expressing WT APP, validating cathepsin B as the target. The specificity of cathepsin B to cleave the WT beta-secretase site, but not the Swe mutant site, of APP for Abeta production explains the distinct inhibitor responses in the different AD mouse models. In contrast to cathepsin B, the BACE1 beta-secretase prefers to cleave the Swe mutant site. Discussion of BACE1 data in the field indicate that they do not preclude cathepsin B as also being a beta-secretase. Cathepsin B and BACE1 could participate jointly as beta-secretases. Significantly, the majority of AD patients express WT APP and, therefore, inhibitors of cathepsin B represent candidate drugs for AD.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA. vhook@ucsd.edu
Vivian
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Gregory
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Mark
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D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000235:genetics; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D011480:Protease Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D055571:Secretory Pathway / Q000187:drug effects; D013379:Substrate Specificity
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D002401:Cathepsin B; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse