Biomedical Engineering Reference
In-Depth Information
(a)
(b)
(c)
(d)
London APP Mice
0.8
0.6
0.4
***
***
0.2
0.0
Control
CA074Me
E64d
Figure 6.7
Inhibitors CA074Me or E64d reduce brain amyloid plaque load in
London APP mice. (a-c) Reduced amyloid plaque observed immunohis-
tochemically in CA074Me- and E64d-treated animals. Micrograph (a)
presents a typical brain section (cortex and hippocampus) from control
untreated APP London mice showing amyloid plaques revealed by anti-
Ab (see arrows pointing to plaques in hippocampus). Micrograph (b) is a
typical section from CA074Me-treated APP London mice showing fewer
amyloid plaques, especially in the hippocampus. Micrograph (c) repre-
sents a section from E64d-treated London APP mice which also contains
fewer amyloid plaques, especially in the hippocampus.
42
(d) Reduction in
amyloid plaque load after treatment with inhibitors. The relative amyloid
plaque load in brain sections obtained was quantitated by computer image
analyses, expressed as a percentage of the tissue area. The relative amyloid
loads are displayed as the mean (% tissue area)
SD, with statistical
significance indicated (***p
o
0.0001, Student's t-test).
gene expression in mice expressing human WT APP suggests that deletion of
the cathepsin B gene decreases b-secretase activity, and that the reduced brain
Ab in these mice may be due to a reduction in b-secretase.
In contrast, knockout of cathepsin B in mice expressing human APP with the
rare Swedish (Swe) and Indiana (Ind) mutations had no effect on Ab. The
difference in reduction in Ab in mice expressing human WT APP mice, but not
in mice expressing human Swedish mutant APP, shows that the transgenic
model can affect cathepsin B gene knockout results. Since most AD patients
express WT APP, these data validate cathepsin B as a target for development of
inhibitors to lower Ab in AD.
Other studies have confirmed the lack of effect of cathepsin B knockout on Ab
in mice expressing APP with the Swe mutation.
49
However, the Mueller-Steiner
