Alzheimer’s Disease
201
inhibitors with therapeutic potential are
preferably small organic molecules with
high speciFcity. The X-ray structure of
BACE1 suggests that its active site is
more open and less hydrophobic than that
of other aspartyl proteases. It may pose
challenges for the development of small-
molecule inhibitors.
5.2
Vaccine Approaches
Another novel approach for Alzheimer
therapy is A
β
immunization. Many studies
have shown that direct immunization with
A
β
peptide or anti-A
β
antibodies can
greatly reduce plaque formation, neuritic
dystrophy, and other AD-like pathology
in APP transgenic mice. One study also
shows that such an immunization strategy
is also effective in reversing behavioral
deFcits in the transgenic mouse model.
It appears that antibodies to A
β
can
enhance A
β
clearance, prevent A
β
Fbril
formation, disrupt A
β
Fbrils, as well as
block A
β
toxicity.
Despite the great effects in mice, there
are serious concerns about the safety of
this approach when used in humans. One
concern is that autoimmunity may occur in
humans, although it has not been reported
in mice. Another major concern is the
toxicity of A
β
42, which can cross the BBB
and seed Fbril formation in the brain,
and therefore may actually promote plaque
formation. In addition, A
β
42 may cause
inflammation and neurotoxicity. A phase
II clinical trial using A
β
42 vaccination was
eventually terminated because of cerebral
inflammation observed in several patients.
The Frst autopsy result from this trial was
just published. It shows exactly the two
sides of this approach. Vaccination has
such a powerful effect that the patient’s
cerebral cortex was almost cleared of A
β
deposition, but the side effect of cerebral
inflammation
was
so
severe
that
the
patient developed meningoencephalitis,
which led to death.
Safer
therapeutic approaches
includ-
ing using nonamyloidogenic/nontoxic A
β
derivatives as an immunogen or passive
immunization with A
β
antibodies are be-
ing developed. One study shows that pas-
sive immunization with (±ab’)
2
fragments
of A
β
-speciFc antibody can clear A
β
in a
mouse model. This is promising because
(±ab’)
2
fragments do not interact with
±c receptors and so will not activate the
cellular-immune response which has been
the major cause for the severe side effects.
5.3
Other Therapeutic Approaches
Several ±AD-approved nonsteroidal anti-
inflammatory drugs (NSAIDs), including
ibuprofen, indomethacin, and sulindac
have been shown to selectively reduce
A
β
42 levels in cultured cells. In addition,
treatment of APP transgenic mice with
ibuprofen reduces A
β
42 levels in the
brain and suppresses plaque pathology.
It appears that NSAIDs can subtly alter
γ
-
secretase activity so that cleavage is shifted
from A
β
42 to A
β
38.
Many studies also indicate that choles-
terol
influences
A
β
metabolism
and
cholesterol-reducing drugs may have a
beneFcial effect on AD. Individuals taking
cholesterol-lowering drugs such as statins
show greatly reduced risk for develop-
ing AD, whereas individuals with elevated
cholesterol are at a higher risk. Statins
and other cholesterol-lowering drugs have
been shown to reduce A
β
levels and A
β
deposition in both cell culture systems and
animal models. The role of cholesterol in
A
β
metabolism appears to be quite com-
plex and the mechanisms are not clear.
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