Alzheimer’s Disease
197
A
β
42/43, but not A
β
40. This effect was
a direct result of the mutation and not
overexpression of the human protein as
the overexpression of the wild-type PS1
did not have any signiFcant effect on A
β
levels. The physiological signiFcance of
the speciFc elevation of A
β
42/43 appears
to be the observation that AD patients with
PS1 mutations show plaques composed
primarily of A
β
42/43. However, all three
PS1 transgenic mice, in contrast to APP
transgenics, revealed no A
β
deposition or
other AD-associated pathology.
Recently, a PS1 mouse model carrying
a PS1-P264L ±AD mutation was devel-
oped using gene-targeting approach. The
gene-targeted models are distinct from
transgenic models because the mutant
gene is expressed at normal levels, in
t
h
ea
b
s
e
n
c
eo
ft
h
ew
i
l
d
-
t
y
p
ep
r
o
t
e
i
n
.
PS1
P264L
/
P264L
mice had normal expres-
sion of PS1 mRNA, but levels of the N- and
C-terminal protein fragments of PS1 were
reduced while levels of the holoprotein
were increased. APP
sw
/
sw
/PS1
P264L
/
P264L
double gene-targeted mice had elevated
levels of A
β
42, sufFcient to cause A
β
de-
position beginning at six months of age.
This was the Frst animal model that exhib-
ited A
β
deposition without overexpression
of APP.
Three transgenic mice that express PS2-
±AD mutation N141I under the control of
PDG±
β
chain promoter, chicken
β
-actin
promoter or the neuron-speciFc enolase
promoter were designed. The Frst two PS2
transgenic mice showed increased levels
of A
β
42 in the brain of 12-month old
mice. The third model utilizing neuron-
speciFc enolase promoter did not show
any difference in A
β
42 levels compared
to the PS2 wild-type transgenic mice and
both had no obvious differences in AD
phenotypes (both had amyloid deposits).
4.3
Tau Transgenic Mice
OneofthedeFcitsofmostADtransgenic
models is the lack of tau pathology. APP
and APP/PS transgenic mice, which ex-
hibit extensive amyloid deposition also
develop hyperphosphorylated tau around
the amyloid deposits but it does not
progress to resemble human N±Ts. This
suggests that some disruption of tau does
occur in response to amyloid accumula-
tion, but it does not progress to resemble
human tauopathy in the mouse model.
The idea that a species barrier prevents
this progression has been proposed sug-
gesting that primates and rodents differ in
their response to injected amyloid not only
in terms of neurodegeneration, but also in
the accumulation of abnormal tau around
the injected amyloid.
The most exciting development in the
tau Feld is the creation of a transgenic
mouse model with robust and repro-
ducible tangle pathology. This transgenic
mouse line, designated JNPL3, express
human four repeat tau containing the
most common ±TDP-17 mutation, P301L,
under the control of the mouse prion pro-
moter. The mice develop motor and behav-
ioral deFcits that are associated with age-
and gene-dosage-dependent development
of congophilic N±T. Tau-immunoreactive
pretangles are found in cortex, hippocam-
pus, and basal ganglia, but at lower levels
than commonly found in human disease.
The tangles are associated with neurode-
generation, especially in the spinal cord
where motor neurons were reduced by ap-
proximately 48%. This mouse has recently
been used in breeding double and triple
transgenic mouse models to produce a
model system that more accurately reca-
pitulates the hallmark pathology of AD
(see further in the text). Recently, another
previous page 197 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 199 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off