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inhibitors was simply not significant because brain Ab was decreased, and
memory was improved. Moreover, as discussed above, deleting the cathepsin B
gene in transgenic mice expressing human WT APP reduces brain Ab; 48 these
data are contrary to the hypothesis that inhibiting cathepsin B may increase
brain Ab 49 because brain Ab decreased upon complete elimination of brain
cathepsin B activity. 48 The cathepsin B inhibitor and knockout data can be
explained by the fact that the animal models used in those experiments
expressed APP containing WT b-secretase site sequence, which is readily
cleaved by cathepsin B as b-secretase to produce brain Ab. Thus, chemical
inhibition of cathepsin B activity or knockout of the cathepsin B gene in such
animals reduces brain Ab production, making Ab degradation unnecessary
because brain Ab need not be degraded if it is not produced.
In the situation of Swe APP expressing mice when cathepsin B inhibition
does not reduce brain Ab, however, cathepsin B inhibition probably does not
significantly impact the degradation of brain Ab. Chronic E64 treatment of
transgenic mice expressing APP containing the Swe and PSI mutation has
no effect on brain Ab levels. 47 If cathepsin B degradation of Ab is significant
in vivo, E64 treatment would be predicted to increase brain Ab because E64 is
a potent inhibitor of cathepsin B, but since that did not occur, these data
do not support the hypothesis of cathepsin B involvement in degradation of
Ab. While viral overexpression of cathepsin B can reduce brain plaque
under certain conditions, the in vivo inhibitor and knockout data do not
support the conjecture that cathepsin B inhibition would reduce brain Ab
degradation and increase Ab levels. On the contrary, E64 inhibition of brain
cathepsin B reduces brain Ab and brain plaque, and improves memory deficits.
These data from multiple groups validate cathepsin B as a target for devel-
opment of drug inhibitors to lower Ab in the majority of AD patients
expressing WT APP.
6.5 Hypothesis that Cathepsin B and BACE1
Participate as Dual b-Secretases for Ab Production
There has been much investigation in the field on the aspartyl protease BACE1
that functions as b-secretase. 11,16-22 With recent data indicating that cathepsin
B is involved in Ab production, 40-44,50,51 this section explains how the com-
bined findings in the field support the hypothesis that cathepsin B and BACE1
function jointly in Ab production. Moreover, the BACE1 results do not pre-
clude cathepsin B as another b-secretase.
6.5.1 BACE1 Prefers to Cleave the Swedish Mutant b-Secretase
Site, Rather Than the Wild-Type b-Secretase Site of APP
The Swedish (Swe) mutant APP possesses two mutant amino acids at the
b-secretase site that lead to increased Ab. This rare mutation is present in an
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