Discovery of the Cysteine Protease Cathepsin B as a Drug Target for Alzheimer’s Disease - Proteinases as Drug Targets - page 157

swim to a hidden platform (Figure 6.6a). Importantly, the reduced latency time
after inhibitor treatment indicates substantial improvement in memory, which
approached that of normal mice. The effectiveness of the inhibitors to improve
memory is also indicated by the reduction in distance traveled to the hidden
platform (Figure 6.6b).
The inhibitor treatment reduced amyloid plaque load in brain, indicating
that the compounds reduced a neuropathological hallmark of AD (Figure
6.7). 42 The CA074Me and E64 inhibitors substantially reduced brain amyloid
plaques (Figure 6.7), and reduced Ab40 and Ab42 levels in brain (Figure
6.8a,b). The CA074Me and E64 inhibitors also reduced brain levels of CTFb
(Figure 6.8c) derived from APP by b-secretase processing (Figure 6.8d).
Importantly, mice remained healthy after inhibitor treatment. These novel
results demonstrate the in vivo effectiveness of these inhibitors of cathepsin B to
improve memory deficit with reduction in brain Ab peptides and amyloid
plaque load in the London APP mouse model of AD expressing human APP
with the WT b-secretase site.
6.4.3.2 No Effect of Cathepsin B Inhibitor Treatment in AD Mice
Expressing the Swedish Mutant b-Secretase Site of APP
In contrast, no inhibitor response was observed in the Swedish mutant APP
mouse model of AD, 42 compared to the substantive effects on memory
improvement in the London AD mice expressing APP with the WT b-secretase
site. Transgenic mice expressing human Swedish mutant APP have been uti-
lized as a mouse model of AD. 3,4,29,46 The Swedish APP possesses the mutant
Asn-Leu residues at the b-secretase cleavage that differs from the wild-type
sequence of Lys-Met at that site. 13
Most interestingly, administration of the inhibitors of cathepsin B,
CA074Me, and E64d to Swedish mutant mice (Swedish mutation in the Lon-
don APP mice, i.e., Swe/London APP mice) had no effect on memory deficit in
the Swedish mutant APP mice, as measured by the Morris water maze test
(Table 6.1). 42 Furthermore, inhibitors had no effect on brain levels of Ab40 and
Ab42, or CTFb (Table 6.1) in mice with the Swedish mutation of APP (Swe/
London APP mice). In addition, E64 had no effect on brain Ab in transgenic
mice expressing the Swe and PS1 (M146L) mutations. 47
6.4.4 Knockout of the Cathepsin B Gene Results in Reduction
in Brain Ab in Mice Expressing APP with the Wild-Type
b-Secretase Site, But Not in Mice Expressing the Swedish
Mutant Site of APP
Notably, knockout of the cathepsin B gene in mice expressing human WT APP
results in substantial decrease in Ab40 and Ab42 by 67% in brain (Figure 6.9),
and decreases in levels of the C-terminal b-secretase fragment (CTFb) derived
from APP. 48 The reduction in CTFb resulting from the absence of cathepsin B