Alzheimer’s Disease
199
mice were not immunoreactive to A
β
42
but instead were stained with antisera
to A
β
40. Similarly, crossing the Tg2576
transgenic mice, which express mutant
APPsw, with mice transgenic for
PS1-
M146L
(PDPS1) revealed 41% increase in
A
β
42/43 levels and formation of A
β
de-
posits in the cortex and hippocampus as
early as 12 weeks of age, compared to de-
velopment of A
β
deposits in Tg2576 mice
of 9–12 months of age and approximately
1.5-fold elevation of A
β
42/43 from birth
in PDPS1 line. The early A
β
deposits were
found to be primarily composed of Fbril-
lar A
β
and resembled compact amyloid
plaques. As the mice aged, these Fbril-
lar deposits did not increase substantially
beyond the 12 months of age. Interest-
ingly, the diffuse deposits appeared only
until later, this is opposite to the general
perception that in AD the compact de-
posits are formed by condensation of the
diffuse material.
Studies on APPxPS1 double transgenics,
therefore, revealed that marginal increases
in A
β
42/43 levels, evoked by PS1 mutant
transgene, can accelerate the deposition
process by several months. As these mice
have a severe A
β
pathology for an extended
time relative to singly transgenic APP
mice, other features of the disease such
as tau abnormalities or major cell loss may
become apparent as the animals age.
Double mutants produced from crossing
JNPL3 transgenic mice expressing mutant
P301L tau with Tg2576 mice expressing
the APPsw mutation offered proof that A
β
influences the development of N±Ts. The
double mutant exhibited N±T pathology
that was substantially enhanced in the lim-
bic system and the olfactory cortex. These
results suggest that APP or A
β
augments
the formation of N±Ts in the regions of
the brain vulnerable to the formation of
these lesions. Recently, a triple transgenic
mouse was generated expressing APPsw,
PS1-M146L, and P301L tau mutant pro-
tein that exhibited both plaques and N±T.
However, other characteristics of AD such
as neurodegeneration and memory loss
have yet to be examined.
Although most of the transgenic mod-
els for AD do not completely recreate
the disease phenotype, they have shown
considerable utility, both for studying the
disease mechanisms and for the prelimi-
nary testing of therapeutic agents, partic-
ularly those that are designed to modulate
A
β
deposition.
5
Potential Treatments
The ultimate goal of AD research is to
prevent disease and/or develop treatments
for this devastating disease. Unfortunately,
there is still no effective treatment avail-
able. Currently, the only ±DA-approved
therapy for AD is cholinesterase inhibitors,
which can enhance cholinergic activity and
temporarily improve cognitive function in
some individuals in the early stages of dis-
ease. However, these drugs only treat the
symptoms but have no impact on progres-
sion of the disease.
Recent advances in dissecting the molec-
ular and cellular mechanisms that are
involved in AD pathogenesis have pro-
vided substantial knowledge for determin-
ing novel targets for drug development.
Several new therapeutic approaches tar-
geted at distinct aspects of the disease are
currently being pursued. Potential ther-
apies include: anti-inflammatory agents,
cholesterol-lowering drugs, antioxidants,
hormonal therapy, and approaches that
inhibit A
β
production or increase A
β
degradation and clearance. Strategies tar-
geted directly at A
β
may be most effective
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