Alzheimer’s Disease
195
AD. 4-hydroxynonenal covalently binds to
APOE, with more binding to E2 and E3
than E4, probably because of the cysteine
residues that are present in E2 and E3.
E2 and E3 may therefore protect neurons
by binding to, and thereby detoxifying,
4-hydroxynonenal.
4
Transgenic Mouse Models of Alzheimer’s
Disease
A
major
hindrance
to
basic
research
into the molecular pathogenesis of AD
has been the absence of a mouse or
rat model. As a result of the identiF-
cation of mutations that cause AD in
humans, this has begun to change. Al-
though initial efforts to make transgenic
models of AD failed, more recent efforts
have recapitulated at least some of the
key features of the disease. Many genet-
ically altered mice have been designed
to reproduce the neuropathology of AD,
however, the majority of them share only
some of the neuropathological and/or cog-
nitive impairment characteristics of AD
mice expressing human forms of the APP,
the PS, APOE and, more recently, tau.
Transgenic mice expressing human APP
develop amyloid plaques, but neurodegen-
eration and neuroFbrillary tangles are not
observed. The Presenilin transgenic mice
produced only increased A
β
42/43 levels
and did not develop signs of AD pathology,
even though the same mutations caused
some of the earliest forms of inherited AD
in humans. Strategies emphasizing tau
resulted in increased phosphorylation of
tau and tangle formation, although amy-
loid plaques were absent. Nevertheless,
crossing transgenic animals expressing
mutated tau and APP has produced a
mouse that closely recapitulates the neu-
ropathology of AD. This section provides a
review of the various murine models and
their role in understanding the pathogen-
esis of AD.
4.1
APP Transgenic Mice
The most extensively studied APP trans-
genic mouse lines are known as PDAPP
and
Tg2576.
The
PDAPP
transgenic
mouse expresses a human APP770 mini
gene containing the V717± ±AD-APP mu-
tation, while Tg2576 expresses human
APP695 that contains the Swedish ±AD-
APP mutation. In PDAPP, expression of
the
APP
gene is under the control of
the human platelet–derived growth fac-
tor (PDG±)-
β
chain neuronal promoter
that targets expression preferentially to
neurons in the cortex, hippocampus, hy-
pothalamus, and cerebellum of the trans-
genic animals. This mouse was made
on a mixed-strain background (C57BL/6,
DBA/2, and Swiss-Webster), while Tg2576
was made on a single C57B6/SJL back-
ground. Expression of the
APP
gene in
Tg2576 mice is under the control of the
prion protein promoter resulting in a less-
limited expression of APP both in the
CNS and the periphery. The success of
both models was due to the high level of
APP expression achieved (
>
10-fold over-
expression of human APP in PDAPP
mouse and
>
6-fold higher expression of
APP in Tg2576 compared to endogenous
murine APP levels). Cortical and limbic
amyloid deposits begin slightly earlier in
the PDAPP mouse: by 3 months of age in
homozygotes and at 6 to 9 months in het-
erozygotes, while in Tg2576 mouse they
occur between 9 to 12 months of age,
elevated A
β
production is observed as
early as 3 months of age. Both models
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