Beta-amyloid (Aβ) in brain is a major factor involved in Alzheimer’s disease (AD) that results in severe memory deficit. site but not the Swe mutant site of APP for Aβ production explains the distinct inhibitor responses in the different AD mouse models. In contrast to cathepsin B the BACE1 β-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 β-secretase. Cathepsin B and BACE1 may participate jointly as β-secretases. Significantly the majority of AD patients express WT APP and therefore inhibitors of cathepsin B represent candidate drugs for AD. effectiveness of these inhibitors of cathepsin B to improve memory deficit with reduction in brain Aβ peptides and amyloid plaque load in the London APP mouse model of AD expressing human APP with the WT β-secretase site. Figure 2 Reduction of Aβ peptides Hupehenine by inhibitors of cathepsin B in AD mice expressing human APP with wild-type β-secretase site but not in mice expressing APP with the Swedish mutant site Figure 3 Reduction of Mouse monoclonal to CD13.COB10 reacts with CD13, 150 kDa aminopeptidase N (APN). CD13 is expressed on the surface of early committed progenitors and mature granulocytes and monocytes (GM-CFU), but not on lymphocytes, platelets or erythrocytes. It is also expressed on endothelial cells, epithelial cells, bone marrow stroma cells, and osteoclasts, as well as a small proportion of LGL lymphocytes. CD13 acts as a receptor for specific strains of RNA viruses and plays an important function in the interaction between human cytomegalovirus (CMV) and its target cells. CTFβ derived from APP after administration of inhibitors of cathepsin B to AD mice expressing the wild-type β-secretase site of APP but not in mice expressing Swedish mutant APP No effect in Swedish mutant APP mice treated with inhibitors of cathepsin B In contrast distinct pharmacogenetic differences in inhibitor response was observed in the Swedish mutant APP mouse model of AD (Hook et al. 2008 compared to the substantive effects on memory improvement in the London AD mice expressing APP with the wild-type β-secretase site. Transgenic mice expressing human Swedish mutant APP have been Hupehenine utilized as a mouse model of AD (Hsiao et al. 1996 Price and Sisodia 1998 Masliah and Rockenstein 2000 Selkoe and Schenk 2002 The Swedish APP possesses the mutant Asn-Leu residues at the β-secretase cleavage that differs from the WT sequence of Lys-Met at that site (Citron et al. 1992 Most interestingly administration of the inhibitors of cathepsin B CA074Me and E64d to Swedish mutant mice (Swedish mutation in the London APP mice ie. Swe/London APP mice) resulted in no effect on memory deficit in the Swedish mutant APP mice as measured by Hupehenine the Morris water maze test of latency time and distance traveled to reach the hidden platform (Figure 1C D) (Hook et al. 2008 Furthermore inhibitors resulted in no change in brain levels of Aβ40 and Aβ42 (Figure 2B C) or CTFβ (Figure 3B) in mice with the Swedish mutation of APP (Swe/London Hupehenine APP mice). The effectiveness of inhibitors in AD mice expressing the wild-type β-secretase site of APP is relevant to the majority of AD patients These novel results demonstrate the unique pharmacogenetic features of the CA074Me and E64d inhibitors to improve memory deficit and reduce brain Aβ in genetic models of AD expressing human Hupehenine APP with the WT β-secretase site. Moreover these cathepsin B inhibitors reduce brain Aβ in normal guinea pigs (Hook et al. 2007 b) indicating that these inhibitors are efficacious in these animals expressing WT APP with production of endogenous levels of Aβ. Significantly since the majority of the AD population expresses WT APP the effectiveness of these inhibitors to reduce Aβ generated from APP with the WT β-secretase site are relevant to the human AD disease condition. Validation of the cathepsin B target by gene knockout studies The CA074Me inhibitor enters cells and is then converted by esterases to CA074 a selective inhibitor of cathepsin B (Towatori et al. 1991 Yamamoto et al. 1992 Therefore the effectiveness of CA074Me to improve memory deficit and reduce Aβ in the London APP mouse model of AD implicates a role for cathepsin B as the candidate inhibitor drug target. To confirm the predicted role of cathepsin B for Aβ production and memory function the effects of cathepsin B gene knockout on Aβ production was investigated (Hook et al. 2009 Knockout of the cathepsin B gene in mice expressing human wild-type APP (WT APP) results in substantial decrease of Aβ40 and Aβ42 in brain (Figure 4A B). The cathepsin B knockout mice also showed a significant decrease in brain levels of the C-terminal β-secretase fragment (CTFβ) derived from APP (Figure 5A) suggesting inhibition of β-secretase activity. In contrast knockout of cathepsin B in mice expressing human APP with the rare Swedish (Swe) and Indiana (Ind) mutations had no effect on Aβ levels in brain (Figure 4C D) and had no effect on CTFβ Hupehenine (Figure 5B). The different effects of cathepsin gene knockout to reduce Aβ in mice expressing human WT APP but not in the genetic.