Biomedical Engineering Reference
In-Depth Information
6.5.4 Ab Production and Secretion in Neurons of BACE1
Knockout Mice
The Roberds study found lower Ab levels in media from cultured brain neurons
obtained from BACE1 knockout mice which implicated participation of
BACE1. 21 However, the Ab in 'conditioned medium' indicates constitutive
secretion of Ab because the neurons were not stimulated to secrete. The
Roberds study did not measure regulated secretion of Ab, and therefore, their
data do not rule out participation of cathepsin B. The same analysis applies to a
study by Cai and colleagues, 11 which also found reduced Ab in conditioned
medium secreted from neurons from BACE1 knockout mice, indicating a role
for BACE1 in the constitutive secretory pathway. The study did not address
regulated secretion and, therefore, does not rule out cathepsin B for Ab pro-
duction in the regulated secretory pathway.
6.5.5 BACE1 and Ab Production in Mice Expressing Normal
Compared to Very High Expression Levels of APP:
Relationship to AD Patients Expressing Physiological
Levels of APP
AD patient brains possess physiologically normal levels of APP. 58 Therefore,
several studies have investigated the effects of BACE1 on Ab production from
endogenous, normal levels of wild-type mouse brain APP, which express APP
containing the human WT b-secretase site sequence. A study by Matsuoka and
colleagues showed that in wild-type mice expressing normal levels of APP
knock out of the BACE1 gene (BACE1-/-) eliminated nearly all of the mouse
brain Ab1-40 and reduced Abx-40 by about 25%. 59 However, that paper also
shows that partial BACE1 gene deletion (BACE1 -/ þ ) has no effect on mouse
brain Ab. A more recent study by the same group showed that overexpression
of BACE1 in wild-type mice has no effect on mouse brain Ab levels, which led
that group to conclude that BACE1 'has minimal effect on the level of endo-
genous Abeta' and that 'other factors must be involved in modulation of Ab
production in adult and aging brain'. 58 Taken together, these data suggest that
levels of BACE 1 appear not to be rate-limiting in the production of Ab pep-
tides. These results raise questions as to the role of BACE1 in producing Ab
from the physiologically normal levels of WT APP in AD patients. Thus, these
data open up the possibility that another protease, such as cathepsin B, may
also be involved in Ab production.
Deleting the BACE1 gene in transgenic mice expressing super high levels of
APP mutated at the g-secretase site (V717F) and the WT b-secretase site
(PDAPP) and resulted in decreased brain Ab levels. 60 PDAPP transgenic mice
express extremely high levels of APP and thus these findings indicate that
BACE1 can function with very high, non-physiological levels of APP. It is
known that protease enzyme activities are dependent on substrate levels. 40,61
Thus, the data in the field suggest involvement of BACE1 in processing high
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