Biomedical Engineering Reference
In-Depth Information
Tg mice expressing hAPPwt
(a)
(b)
A 42
40
A
6
50
5
40
4
30
3
**
**
20
2
10
1
0
0
Cat.B +/+ Cat.B -/-
Cat.B +/+ Cat.B -/-
Figure 6.9
Knockout of the cathepsin B gene in transgenic mice expressing human
wild-type APP (WT APP) reduces brain Ab40 and Ab42. (a) Ab40 levels
in brain. The wild-type Cat B+/+ and knockout Cat B-/- mice expressing
human wild-type APP (WT APP) contained brain Ab40 levels of
40.0
21% and 13.6
22% nM, respectively (significant, **p
o
0.007).
Knockout of the cathepsin B gene resulted in a 66% reduction in brain
Ab40 in mice expressing WT APP.
48
(b) Ab42 levels in brain. The Cat
B+/+ and Cat B-/- mice expressing hAPPwt contained brain Ab42 levels
of 4.8
21% and 1.5
24% nM, respectively (**significant, p
o
0.007).
Knockout of the cathepsin B gene resulted in a 68% reduction in brain
Ab42 in animals expressing WT APP.
48
studies did not examine the effects of cathepsin B knockout in mice expressing
WT APP.
Furthermore, gene silencing of cathepsin B by siRNA in normal hippo-
campal brain neurons (in primary culture) expressing WT APP reduces the
amount of Ab in the regulated secretory pathway.
50
These studies also showed
that the CA074Me inhibitor reduces Ab in the regulated secretory pathway of
rat hippocampal neurons, indicating a role for cathepsin B in Ab production.
6.4.5 Cathepsin B Degradation of Ab is Not Significant In Vivo
One report speculated that cathepsin B may be important for the extracellular
degradation of brain Ab in vivo and that inhibiting cathepsin B may increase
brain Ab and thereby promote memory loss and AD.
49
That hypothesis was
based in large part on data showing that doubling brain cathepsin B activity by
its expression via injection of a lenti-cathepsin B vector into the brains of
transgenic mice expressing APP with the Swe mutation resulted in decreased
brain plaque in the area receiving the injection. The cathepsin B inhibitor data
discussed in this chapter argue against that hypothesis because the inhibitors
reduced brain cathepsin B activity, decreased brain Ab in the guinea pig and
transgenic APPLon mice, and also improved memory deficits and reduced
brain amyloid plaque in the transgenic APPLon mice. Any inhibition of
cathepsin B's ability to degrade Ab that may have occurred due to the
