198
Alzheimer’s Disease
P301L tau transgenic model has been de-
scribed that develops fveFold increase in
the numbers oF N±T soon aFter 18 days aF-
ter the intracerebral injection oF A
β
42 into
the CA1 region oF the hippocampus. These
experiments indicate that an interaction oF
β
-amyloid with the P301L tau mutation
accelerates N±T Formation.
4.4
Apolipoprotein E Transgenic Mice
A consistent consequence oF carrying the
APOE4
allele is an increased number oF
amyloid plaques in the brain and more
abundant amyloid deposition in the cere-
bral vasculature. The mechanism by which
APOE4
contributes to the development oF
neurodegeneration remains unknown, al-
though the evidence suggests that this
may be linked to the ability oF APOE to
interact with the amyloid
β
peptide and
influence its concentration and structure.
Recent studies with transgenic mice that
overexpress the human APOE isoForms
APOE2, APOE3, and APOE4 in a PDAPP
hemizygous mouse (Apoe-/- background)
show that isoForms that are known to in-
crease the risk oF AD enhance amyloid load
and increase the neuritic pathology associ-
ated with fbrillar plaque development in
aged animals (by 15 months oF age APOE4
expressing mice having a 10-Fold greater
amyloid burden than APOE3 mice). The
time course oF A
β
deposition, A
β
levels,
structure, and anatomic and subcellu-
lar distribution showed proFound age-,
species-, and isoForm-dependent eFFect oF
APOE. It was also Found that APOE not
only impacts on the nature oF aggregated
A
β
, but also on the clearance oF soluble A
β
From the brain across the blood–brain bar-
rier (BBB). A
β
40 was rapidly cleared From
the brain, while A
β
42 was cleared much
less eFFectively, supporting the idea that
A
β
42 production may Favor amyloid depo-
sition due to a reduced clearance across
the BBB. However, A
β
clearance was not
APOE isoForm specifc.
These recent fndings are consistent
with earlier work on Apoe null mice. When
Tg2576 and PDAPP mice were crossed
with Apoe null mice it was revealed that
theabsenceo
FApoea
l
teredthequan
t
i
ty
,
character, and distribution oF A
β
deposits
in the transgenic animals, confrming that
APOE aFFects the neuropathological phe-
notype in AD brains. The A
β
deposition is
signifcantly reduced and is not thioflavine-
S-positive.
4.5
Modulating and Enhancing the Phenotype:
Transgenic Crosses
One oF the great advantages oF transgenic
animals is that diFFerent mice can be mated
together so that the eFFect oF multiple
transgenes on the disease phenotype can
be observed. In particular, since most
transgenic AD models do not exhibit all
the pathological Features oF AD, diFFerent
crosses have been made in order to design
a model that will more closely describe
the
pathology,
neurodegeneration, and
memory loss seen in AD patients.
Double transgenic mice that carry
PS1-
A246E
and
APPsw
±AD mutations show
an elevated A
β
42/A
β
40 ratio in brain ho-
mogenates compared to the ratio observed
in
transgenic
mice
expressing
APPsw
alone or transgenic mice coexpressing
wild-type human
PS1
and
APPsw
. In addi-
tion, double transgenic mice
APPswxPS1-
A246E
developed numerous amyloid de-
posits much earlier (9 months oF age)
than age-matched mice expressing
APPsw
(18 months oF age) and wild-type
huPS1
and
APPsw
alone. Interestingly, the major-
ity oF A
β
deposits in the double transgenic
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