194
Alzheimer’s Disease
prominent behavioral changes early in the
disease. The neuropathology associated
with FTDP-17 is characterized by large
numbers of NFT but no senile plaques.
Mutations in the tau gene in FTDP-17 can
alter splicing and produce a shift from
the short tau isoform with three repeats
to the longer isoform, which contains
four repeats. Several other point mutations
have been discovered in the coding region
of tau that impact the functional integrity
of the tau protein itself, P301L being the
most common. So far, genetic analysis has
not linked tau mutation directly to AD, but
tau dysfunction may still have a signi±cant
role to play in the disease, if not in its
initiation, then in its progression.
3.6
Apolipoprotein E
Apolipoprotein E is a 299 amino acid
glycoprotein with a molecular weight of
34 kD. Its N-terminal domain consists
of four amphipathic
α
-helices and the
C-terminal domain contains most of the
lipid-binding activity. APOE is a major
apolipoprotein that regulates cholesterol
uptake and release. The CNS contains
high levels of APOE with abundance only
second to the liver. In the CNS, APOE is
synthesized predominantly by astrocytes
and is secreted into the CSF, where it is a
major lipid carrier.
APOE appears to have multiple func-
tions in the brain – any or all of which
could potentially influence AD pathogene-
sis. The molecular mechanisms by which
APOE protein is involved in AD patho-
genesis are unclear because reports on
the allele-speci±c effects of APOE are con-
troversial. Nevertheless, numerous studies
have demonstrated that APOE can affect
AD pathogenesis either by influencing A
β
deposition or by a direct effect on neuronal
survival. APOE is a major component of
senile plaques and speci±cally binds to sol-
uble A
β
s. Allele-speci±c differences in A
β
binding, aggregation, and ±brillogenesis
have been reported. Most histopathologic
studies demonstrated a correlation be-
tween senile plaque density and
APOE4
allele dose in AD. Animal studies also show
that APOE has isoform-speci±c effects on
A
β
deposition and plaque formation (see
Sect. 4.4).
There is also evidence that different
alleles of
APOE
have different effects on
neurite extension, neuronal survival, and
the cell’s response to oxidative stress.
In
vitro
studies with primary neurons and
neuronal cell cultures show that lipid-
bound E3 promotes neurite extension,
while E4 is neutral or inhibitory. These
in
vitro
±ndings are consistent with reported
defects in neuronal remodeling in AD
brains carrying an E4 allele. APOE can
have allele-speci±c differences on both
neurotoxic or neuroprotective activities.
High levels of APOE or some APOE
synthetic peptides were shown to cause
neurite degeneration or neuronal death
in cultured cells, with the E4 having the
most neurotoxic effects. On the other hand,
APOE appears to play a role in protection
against
oxidative
stress,
a
prominent
phenomenon in AD pathogenesis. Apoe
-/- mice exhibit increased markers of
lipid peroxidation within the brain and
appear to have increased susceptibility
to
neuronal
damage.
Different
APOE
alleles are shown to have isoform-speci±c
neuroprotective effects (E2
>
E3
>
E4) on
oxidative cytotoxicity caused by hydrogen
peroxide,
or
A
β
peptides.
A
possible
mechanism for the different antioxidant
activities of the
APOE
alleles is their ability
to detoxify 4-hydroxynonenal, a neurotoxic
lipid-peroxidation product that is believed
to play a key role in neuronal death in
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