196
Alzheimer’s Disease
develop
β
-amyloid deposits (in hippocam-
pus and neocortex but limited in striatum
and cerebellum), and the deposits are as-
sociated with dystrophic neurites, punctate
immunoreactivity to hyperphosphorylated
tau, astrocytosis, microgliosis, and vascu-
lar amyloidosis. The elevation of A
β
in the
Tg2576 mouse correlates with the appear-
ance of memory and learning deFcits in
the oldest group of transgenic mice as well.
However, both APP transgenic models fail
to show all the pathological features of hu-
man AD; no signiFcant neuronal loss and
no formation of N±Ts were observed in
either line.
Several other APP transgenic models
were generated in order to obtain a com-
plete or more comprehensive picture of the
hallmarks of AD. The TgAPP22 transgenic
mice overexpress a double mutant APP
with Swedish (K670N, M671L) and Lon-
don (V717I) ±AD mutations in cis, while
TgAPP23 only carries the Swedish muta-
tion. In both models, the human APP751
isoform is used and its expression is under
the control of the murine Thy-1 promoter.
The TgAPP22 mice show twofold overex-
pression of the transgene over endogenous
APP, and A
β
deposits were detected in the
neocortex and hippocampus at 18 months
of age, while the TgAPP23 has higher, sev-
enfold overexpression of human APP and
typical A
β
plaques appear at the age of six
months. Interestingly, these two murine
AD models showed differences in plaque
type; the majority of amyloid deposits in
TgAPP22 mice brains are of the ‘‘diffuse’’
type, while in the TgAPP23 mice almost
all extracellular amyloid deposits were Fb-
rillar. Both substantial neurodegeneration
and a reduction of neuron numbers were
apparent in TgAPP23. In 14–18 months
old TgAPP23 neuronal loss was 14% and
reached 25% in mice with high A
β
plaque
load. Additional pathological features in-
cluded dystrophic neurites surrounding
the plaques, hyperphosphorylated tau, but
no N±Ts developed.
Each of the models described above
is
remarkable
in
that
the
anatomical
pattern
of
plaque
formation
parallels
that seen in human AD. ±urthermore,
the morphology of amyloid plaques in
aged APP-transgenic mice recapitulates
amyloid pathology in human AD: the
plaques span a continuum from diffuse
A
β
deposits to compact core plaques
with inflammation and neuritic dystrophy.
However, none of these models reflects a
complete picture of the neuropathology
of AD.
4.2
Presenilin 1/2 Transgenic Mice
Several PS1 transgenic mice have been
created to study presenilin biology
in vivo
.
Th
e
s
em
i
c
ed
i
f
f
e
rinth
ep
r
om
o
t
e
rand
the strains of mice used, but are similar in
achieving high levels of protein production
(1–3 fold over endogenous) in neuronal
regions of the brain. Knockin transgenes
were created expressing either the wild-
type
human
PS1
or
PS1
containing
the
±AD
mutation
A246E
under
the
transcriptional control of the human Thy-
1 promoter in PS1 null background. Both
mice rescued the PS1 knockout mouse
from embryonic lethality, conFrming that
PS1 mutation does not cause a loss of
function of PS1 protein but has similar
physiological properties as wild-type PS1.
A second PS1 transgenic model expressing
human mutant (M146L or M146V) and
wild-type PS1 was generated under the
control of the PDG± promoter. All three
PS1 transgenics showed similar results:
overexpressing mutant PS1 in the brains
of transgenic mice lead to the elevation of
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