200
Alzheimer’s Disease
given the fact that A
β
deposition is the
central and fundamental event that causes
AD. Other approaches affecting down-
stream events in the neurodegenerative
process are likely to be used as supple-
mentary treatments.
5.1
Secretase Inhibitors
Two prime targets for drug development
are
β
-and
γ
-secretases, the two enzymes
that process APP to A
β
. Inhibitors to
these two proteases are expected to have
the
greatest
A
β
-lowering
effect
since
inhibiting either enzyme can completely
inhibit A
β
generation.
γ
-secretase is considered to be central
to AD pathogenesis because altering its
activity invariantly favors A
β
42 produc-
tion and causes AD. The major concern
in developing a drug that targets the
γ
-
secretase is its potential for side effects.
It is clear that
γ
-secretase is important
for several physiological functions through
its role as the protease that mediates the
intramembranous cleavage of a number
of TM proteins, including Notch. One
possible solution is to develop an in-
hibitor that selectively lowers A
β
(A
β
42
in particular) production without signif-
icantly affecting the cleavage of other
γ
-secretase substrates. The development
of such inhibitors has been reported.
Another possible approach is partial in-
hibition of
γ
-secretase activity, at inhibitor
concentrations that reduce A
β
produc-
tion without affecting Notch signaling.
Indeed, it has been shown that compounds
with no reported selectivity allow signiF-
cant A
β
reduction without changing the
Notch-related function. Some inhibitors,
however, are reported to preferentially in-
crease A
β
42 production when used at low
concentrations.
Most evidence suggests that
β
-secretase
(BACE1) may be a better therapeutic target
than
γ
-secretase. BACE1 knockout mice
do not generate A
β
,bu
ta
r
eo
th
e
rw
i
s
e
healthy and fertile without obvious deFcits
in the basal, neurological, and physio-
logical functions. In addition, the X-ray
structure of the BACE1 protease domain
has been solved and should provide valu-
able knowledge for inhibitor design.
Although the knockout data are re-
assuring that the detrimental effects of
inhibiting
β
-secretase may be minimal,
concerns regarding the possible side ef-
fects remain. ±irst, there are likely other
β
-secretase substrates since it is counterin-
tuitive to assume that BACE1 has evolved
just to generate A
β
. Indeed, one recent
study suggests that
β
-secretase may be re-
sponsible for the cleavage and secretion of
a Golgi resident sialyltransferase. It is very
important to identify these substrates be-
cause they are valuable for predicting the
possible side effects of BACE1 inhibitors.
It will also be important to know the phe-
notype of BACE1/2 double knockout mice.
Although BACE2 is not primarily involved
in A
β
generation, it may have an impor-
tant physiological role and inhibitors of
BACE1 may also inhibit BACE2 because
of the high degree of homology between
these two proteins.
While inhibitors to both secretases may
potentially be effective in AD treatment,
the challenges facing drug development
are signiFcant. The inhibitors need to be
highly selective for the target enzyme and
target substrate to reduce possible side
effects to a minimum. The inhibitors need
to be able to efFciently cross the BBB.
Potent peptide-based inhibitors to BACE1
have been developed. However, such large
compounds are not viable drug candidates
because they will not penetrate the BBB
to a sufFcient extent. Instead, the enzyme
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