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The Journal of Neuroscience, December 1, 2002, 22(23):10083-10087
BRIEF COMMUNICATION
Apolipoprotein E4 Influences Amyloid Deposition But Not Cell
Loss after Traumatic Brain Injury in a Mouse Model of Alzheimer's
Disease
Richard E.
Hartman1, 2, 3,
Helmut
Laurer4,
Luca
Longhi4,
Kelly R.
Bales5,
Steven M.
Paul5, 6,
Tracy K.
McIntosh4, and
David M.
Holtzman1, 2, 3, 7
1 Center for the Study of Nervous System Injury,
2 Alzheimer's Disease Research Center,
3 Department of Neurology, Washington University School of
Medicine, St. Louis, Missouri 63110, 4 Department of
Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania
19104-6316, 5 Neuroscience Discovery Research, Eli Lilly
and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285, 6 Department of Pharmacology, Toxicology, and Psychiatry,
Indiana University School of Medicine, Indianapolis, Indiana 46285, and
7 Department of Molecular Biology and Pharmacology,
Washington University School of Medicine, St. Louis, Missouri 63110
 |
ABSTRACT |
The  4 allele of apolipoprotein E
(APOE) and traumatic brain injury (TBI) are both
risk factors for the development of Alzheimer's disease (AD). These
factors may act synergistically, in that APOE4+ individuals are more likely to develop dementia after TBI. Because the
mechanism underlying these effects is unclear, we questioned whether
APOE4 and TBI interact either through effects on
amyloid- (A) or by enhancing cell death/tissue injury. We
assessed the effects of TBI in PDAPP mice (transgenic mice that
develop AD-like pathology) expressing human APOE3
(PDAPP:E3), human APOE4 (PDAPP:E4), or no
APOE (PDAPP:E /). Mice were subjected to a unilateral
cortical impact injury at 9-10 months of age and allowed to survive
for 3 months. A load, hippocampal/cortical volumes, and hippocampal CA3 cell loss were quantified using stereological methods. All of the
groups contained mice with A-immunoreactive deposits (56% PDAPP:E4, 20% PDAPP:E3, 75% PDAPP:E/), but thioflavine-S-positive A (amyloid) was present only in the molecular layer of the dentate gyrus in the PDAPP:E4 mice (44%). In contrast, our previous studies showed that in the absence of TBI, PDAPP:E3 and PDAPP:E4 mice have
little to no A deposition at this age. After TBI, all of the A
deposits present in PDAPP:E3 and PDAPP:E/ mice were diffuse plaques. In contrast to the effect of APOE4 on amyloid,
PDAPP:E3, PDAPP:E4, and PDAPP:E/ mice did not differ in the amount
of brain tissue or cell loss. These data support the hypothesis that APOE4 influences the neurodegenerative cascade after TBI
via an effect on A.
Key words:
Alzheimer's disease; amyloid; APP; traumatic brain
injury; apoE; hippocampus
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INTRODUCTION |
The 4 allele of apolipoprotein E
(APOE) and traumatic brain injury (TBI) are both risk
factors for the development of Alzheimer's disease (AD). It was first
found that APOE4 was a risk factor for AD in 1993 (Strittmatter et al., 1993 ), and numerous studies have confirmed this
association. Several studies have found that individuals who sustained
moderate to severe head injury are more likely to develop dementia and
AD (Mayeux et al., 1993, 1995; Plassman et al., 2000). These risk
factors appear to act synergistically, in that individuals who are
APOE4+ are even more likely to develop dementia if they
sustain TBI at some time in their life. For example, APOE4+ individuals were 10 times more likely to develop AD
after TBI than those who were APOE4, whereas
APOE4 in the absence of injury was associated with only
twice the risk (Mayeux et al., 1995; Tang et al., 1996).
Although the mechanisms underlying these effects are unclear, some
evidence suggests that both APOE4 and TBI may influence the
risk of AD via interactions with the amyloid- (A) peptide. For
example, A deposition can be found in ~30% of people who die
shortly after TBI (Roberts et al., 1991, 1994); a significant percentage of these patients are APOE4+ (Nicoll et al.,
1995, 1996). In addition, analysis of CSF from TBI patients
revealed elevated levels of A1-42 for up to a
week after TBI, in comparison with both controls and AD patients
(Raby et al., 1998; Emmerling et al., 2000). In an evaluation of the
effect of APOE3, APOE4, or APOE/
in transgenic (TG) mice after TBI, greater mortality was observed in
APOE4 mice, whereas APOE3 mice exhibited better neurological function between 3 and 11 d after TBI (Sabo et al., 2000). Although APOE3 mice had less tissue loss after TBI
than APOE/ or wild-type mice, there was no
significant difference in tissue loss comparing APOE3
with APOE4 mice. The mice studied did not express human
amyloid precursor protein, so A deposition did not occur (Sabo et
al., 2000).
Because the mechanism by which the APOE genotype and TBI
interact to influence dementia remains unresolved, we questioned whether APOE4 and TBI interact through effects on A,
enhancement of cell death or tissue injury, or both. We used a well
characterized model of TBI (Smith et al., 1995) and assessed the
histological outcome in PDAPP mice (a TG mouse that develops AD-like
pathology) that either lack apoE or express human APOE3 or
APOE4.
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MATERIALS AND METHODS |
PDAPP mice expressing amyloid precursor protein (APP) with a
mutation that causes familial AD
(APPV717F) (Games et al., 1995) but lacks
the mouse APOE gene (PDAPP+/+, APOE/) (Bales
et al., 1997) were bred with mice that express human APOE
under control of the glial fibrillary acidic protein (GFAP) promoter
(GFAP-APOE3 and GFAP-APOE4) (Sun et al.,
1998). The GFAP-APOE3 and GFAP-APOE4 mice were
all on a C57BL/6 mouse APOE/ background. The breeding
produced three types of TG mice (Holtzman et al., 2000): PDAPP+/,
APOE/ (PDAPP:E/), PDAPP+/, APOE3+/
(PDAPP:E3), and PDAPP+/, APOE4+/ (PDAPP:E4). Human APOE3 and APOE4 TG mouse lines used in this
experiment were matched for APOE levels (Sun et al., 1998). The mice
were subjected to a controlled cortical impact injury (left hemisphere)
(Smith et al., 1995) at 9-10 months of age, while under pentobarbital
(65 mg/kg) anesthesia. This injury results in underlying cortical damage with shrinkage of the hippocampus and CA3 cell loss. Mortality rates immediately after TBI were similar in all groups (~25%), resulting in sample sizes of n = 4 PDAPP:E/,
n = 10 PDAPP:E3, and n = 9 PDAPP:E4. At
12-13 months (3 months after injury), all mice were killed; their
brains were removed, fixed, frozen, and sliced into 50 µm coronal
sections from the genu of the corpus callosum through the caudal extent
of the hippocampus (Holtzman et al., 2000). Three sets of sections,
each containing every sixth slice, were collected from each brain. The
sections were then mounted and stained with pan anti-A antibody
(Biosource, Camarillo, CA), cresyl violet, or
4',6'-diamidino-2-phenylindole (DAPI). Animals with A-immunoreactive
(IR) deposits were further analyzed using the Cavalieri point-counting
method with stereological software (Stereo Investigator;
MicroBrightField Inc., Colchester, VT) to quantify the area covered by
A-IR deposition (A load) as described previously (Holtzman et
al., 2000).
To obtain volume estimates of the hippocampus and cortex, cresyl
violet-stained sections were analyzed. Hippocampal measurements were
taken from every sixth section through the entire structure; cortical
measurements were taken from the first three anterior sections
containing hippocampal tissue. The cortical region of interest was
defined as cortical tissue dorsal to the superior extent of the
thalamus. The volumes of the hippocampus and defined cortical region
were determined using the Stereo Investigator software. The percentage
of hippocampal and cortical tissue lost (ipsilateral vs contralateral
to injury) was calculated for each group.
In most animals, the inferior blade of the CA3 hippocampal field
exhibited a focal lesion ipsilateral to the injury, also noted in
rodent models of TBI (Nakagawa et al., 1999). CA3 neuronal counts were
obtained using DAPI-stained sections through the entire extent of the
hippocampus. A randomly selected subset of brains was analyzed
(n = 4 PDAPP:E/; n = 5 PDAPP:E3;
n = 5 PDAPP:E4), and measurements were taken from all
sections that contained CA3 neurons. In each section, the inferior
blade of CA3 was traced using the computer. Estimates of neuronal
numbers were obtained with the optical fractionator technique
using Stereo Investigator software. The area was traced with a 4×
lens, and neurons were counted throughout the traced area using
systematic random sampling with a 100× lens.
The data were analyzed using Statistica 6.0 (Statsoft Inc., Tulsa, OK),
and  levels of p < 0.05 were set for significance. The frequency of A deposition was analyzed using
 2 analysis. The percentage of the
hippocampus covered by A-IR was analyzed with a two-way ANOVA that
included one between-subjects factor (genotype: PDAPP:E3 vs PDAPP:E4 vs
PDAPP:E/) and one within-subjects factor (hemisphere: ipsilateral
vs contralateral to impact). Cortical and hippocampal volume estimate
data were analyzed with two-way ANOVAs that included one
between-subjects factor (genotype: PDAPP:E3 vs PDAPP:E4 vs
PDAPP:E/) and one within-subjects factor (hemisphere: ipsilateral
vs contralateral to impact). CA3 neuronal counts were analyzed with a
two-way ANOVA that included one between-subjects factor (genotype:
PDAPP:E3 vs PDAPP:E4 vs PDAPP:E/) and one within-subjects factor
(hemisphere: ipsilateral vs contralateral to impact).
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RESULTS |
A analysis
Frequency and pattern of A deposition
We found previously that PDAPP mice expressing human
APOE3 or APOE4 do not develop A deposition
until ~15 months of age, when PDAPP:E4 mice in particular begin
depositing A and amyloid (Holtzman et al., 2000; Fagan et al.,
2002). In contrast, after TBI, we found that a high percentage of
brain-injured PDAPP:E4 mice had A deposition by 12-13 months of
age. In the PDAPP:E4 mice, 55.6% had A-IR deposits within the
hippocampus and 44% had thioflavine-S-positive A (fibrillar
amyloid) in the molecular layer (ML) of the dentate gyrus (Table
1). Among the PDAPP:E3 mice, only 20%
had hippocampal A-IR deposits, all of which were diffuse plaques. No
PDAPP:E3 mice had fibrillar amyloid deposition. Significantly more
PDAPP:E4 mice had ML A-IR deposits compared with PDAPP:E3 mice
(2, p < 0.02) (Fig.
1). This is notable because A
deposition in the ML of PDAPP mice coincides with the onset of
fibrillar A deposition and neuritic plaque formation (Holtzman et
al., 2000; Fagan et al., 2002). Thus, only the PDAPP:E4 mice developed
neuritic plaque formation after TBI at this age. Assessment of
A40 and A42
immunostaining of PDAPP:E3 and PDAPP:E4 mice revealed the same pattern
of staining as that seen with the pan-A antibody (data not shown).
Qualitatively, the same differences between PDAPP:E3 and PDAPP:E4 mice
were noted with these antibodies. As in previous studies with PDAPP and
other human APP TG mice, neurofibrillary tangles were not seen. Because
PDAPP:E3 and PDAPP:E4 mice have little to no A deposits at 12-13
months of age in the absence of TBI (Holtzman et al., 2000; Fagan et
al., 2002), TBI appears to accelerate A deposition in the form of
amyloid in the presence of human APOE4 to a greater extent
than APOE3. Consistent with previous reports (Holtzman et
al., 2000; Fagan et al., 2002), three of the four PDAPP:E/ mice had
hippocampal diffuse A-IR deposits at 12 months of age; however, none
were fibrillar.
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Figure 1.
A, Almost one-third of the total
hippocampal A load was contained in the ML of the dentate gyrus in
PDAPP:E4 mice. Localization of A deposition in the ML is associated
with the formation of fibrillar amyloid. In contrast, no ML A-IR
deposits were found in PDAPP:E3 or PDAPP:E/ mice 3 months after
TBI. B, Photomicrographs show A staining in the
hippocampus (arrowheads delineate the borders of the
ML).
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Hippocampal A load
Analysis of all three groups revealed no significant difference
between the two hemispheres in the amount of A immunoreactivity. There was a significant main effect of genotype in that, consistent with previous reports (Holtzman et al., 2000; Fagan et al., 2002), PDAPP:E/ mice had a significantly greater A load than PDAPP:E3 or PDAPP:E4 mice (p < 0.0001). However, the
A deposits present in PDAPP:E/ mice consisted of only
thioflavine-S-negative, diffuse A (i.e., nonfibrillar, nonamyloid
deposits). The amount of diffuse A in PDAPP:E/ mice after TBI
was not clearly increased compared with PDAPP:E/ mice in the
absence of TBI (Holtzman et al., 2000; Fagan et al., 2002). A separate
PDAPP:E3 versus PDAPP:E4 analysis revealed a significant main effect of
genotype (PDAPP:E4 > PDAPP:E3; p < 0.05) but no
significant hemisphere effect. Approximately 35% of the
hippocampal A load in PDAPP:E4 mice was contained within the ML,
whereas no PDAPP:E3 or PDAPP:E/ mice had ML deposition. Analysis of
the percentage of A deposition within the ML of the dentate gyrus
revealed a significant main effect of genotype (PDAPP:E4 > PDAPP:E3 and PDAPP:E/; p < 0.006) (Fig. 1).
Cortical and hippocampal volume estimates
Cortex
After TBI, the cortical volume ipsilateral to impact was
significantly less than the contralateral, nonimpacted hemisphere for
all groups (p < 0.0001) (Fig.
2). A main effect of genotype revealed
that PDAPP:E4 mice had slightly but significantly more cortical tissue
bilaterally than PDAPP:E3 or PDAPP:E/ mice, which did not differ
(p < 0.001). The hemisphere-genotype
interaction was not significant. The percentage of tissue loss in the
cortex ipsilateral versus contralateral to injury revealed no
significant genotype differences.
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Figure 2.
A, No group differences were found
for percentage of area loss in either the cortex or the hippocampus.
B, Photomicrograph shows a cresyl violet-stained brain
section with atrophy of the cortex and hippocampus in the injured
hemisphere 3 months after TBI.
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Hippocampus
After TBI, the hippocampus ipsilateral to impact was significantly
smaller than the contralateral hippocampus for all groups (p < 0.008) (Fig. 2). A main effect of the
genotype revealed that PDAPP:E3 mice had slightly but significantly
less overall hippocampal tissue bilaterally than PDAPP:E4 or
PDAPP:E/ mice, which did not differ (p < 0.001). The hemisphere-genotype interaction was not significant. The
percentage of tissue loss in the hippocampus ipsilateral versus
contralateral to injury revealed no significant genotype differences.
Neuronal counts (CA3 inferior blade)
After TBI, the inferior blade of CA3 ipsilateral to injury had
significantly fewer neurons (~35% less) than the uninjured hemisphere for all groups (p < 0.0005) (Fig.
3). There were no significant genotype
main effects or interactions. The percentage of CA3 cell loss revealed
no significant genotype differences.
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Figure 3.
A, No group differences were found
for neuronal loss within the inferior blade of CA3. B,
Photomicrograph shows a DAPI-stained brain section revealing atrophy of
the CA3 region (arrowheads delineate the borders of the
CA3 inferior blade) 3 months after TBI.
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DISCUSSION |
Our previous work (Holtzman et al., 2000; Fagan et al., 2002)
demonstrated that A deposition in PDAPP mice that express human APOE normally does not begin until ~15 months of age,  6
months later than in animals expressing murine apoE. The
appearance of A-IR deposits by 12-13 months in the current study
suggests that TBI accelerated the A deposition process in the
presence of human APOE4. Furthermore, only PDAPP:E4 mice had
significant A-IR deposits in the ML of the dentate gyrus within 3 months of TBI. These ML deposits are associated with
thioflavine-S-positive staining, indicating the conversion of soluble
A to a -sheet conformation and neuritic plaque formation. As in
our previous studies, PDAPP:E/ mice had higher levels of A
deposition than PDAPP:E3 or PDAPP:E4 mice, yet none of these deposits
consisted of true amyloid. Thus, although the presence of APOE
facilitates A fibril formation, human APOE is likely also to play a
role in A clearance. Our results suggest that TBI and
APOE4 (compared with APOE3) interact to result in
greater and earlier amyloid deposition. Overall, these data suggest
that the association with APOE4 and higher risk for
cognitive impairment and AD after TBI may in part be attributable to
APOE-A interactions.
Human studies have shown that both short- and long-term recovery
from TBI seem to be influenced by APOE. APOE4+ individuals scored significantly worse on neuropsychological tests 3 weeks after
mild to moderate TBI than APOE4 individuals (Liberman et al., 2002), and APOE4 was predictive of longer periods of
unconsciousness and worse clinical outcome after TBI (Friedman et al.,
1999). Furthermore, APOE4+ individuals were twice as likely
as APOE4 individuals to be dead, comatose, or severely
disabled 6 months after TBI (Teasdale et al., 1997). In addition to the
poor general clinical outcome associated with APOE4, memory
performance within 6 months of head injury was worse in
APOE4+ patients compared with APOE4 patients
(Crawford et al., 2002), whereas APOE4 led to worse motor
function after TBI (Lichtman et al., 2000). Mild, repetitive head
injury also appears to interact with APOE. APOE4+ professional boxers had significantly worse neurological scores on a
test of chronic brain injury that encompassed cognitive, motor, and
behavioral domains than boxers who were APOE4 (Jordan et
al., 1997). Similarly, older APOE4+ professional football
players scored lower on cognitive tests than APOE4 players
(Kutner et al., 2000).
Clinical and experimental TBI is also associated with accelerated A
deposition (Roberts et al., 1991), with an even greater effect observed
in APOE4+ individuals on both parenchymal and vascular A
deposits (Nicoll et al., 1995, 1996; Macfarlane et al., 1999; Leclercq
et al., 2002). A deposition is also accelerated after
seizure-induced neurodegeneration, even in young APOE4+ subjects (Gouras et al., 1997). In addition to human studies, the
effects of TBI on A and AD pathology have also been studied using TG
mouse models of AD. Smith et al. (1998) reported that TBI in PDAPP mice
resulted in an 84% loss of CA3 neurons compared with only a 36% loss
in non-TG mice. Nakagawa et al. (1999, 2000) have reported that TBI in
both young and old PDAPP mice induces atrophy and reduces A
deposition in the ipsilateral versus contralateral hippocampus. A
deposition after repetitive brain injury using different APP TG mice
(Tg2576) and milder cortical impact has also been reported (Uryu et
al., 2002). Our study extends these findings and demonstrates the
amyloid-promoting effects of human APOE4.
How TBI results in an isoform-dependent increase in amyloid deposition
is not clear. Both in vitro and in vivo studies
demonstrate that APOE can interact with A and influences the
probability of whether A will aggregate in a -sheet conformation,
resulting in neuritic toxicity (for review, see Wisniewski et al.,
1997; Holtzman, 2001). The level of apoE plays a significant role in this effect, because mouse apoE regulates A deposition in a gene dose-dependent manner in vivo (Bales et al., 1997). The
effects of TBI on APOE-A interactions may be secondary to an
increase in APOE levels after TBI as well as alterations in
APOE-dependent A clearance. An increase in APOE levels has been
noted after multiple types of brain injury coincident with glial
activation (Teter, 2000). In addition to neuronal degeneration, there
is cellular reorganization with increased gliosis and alterations in
the vasculature. APOE can potentially interact with different apoE
receptors as well as the extracellular matrix. Because both of these
factors change in regions of injury, APOE-mediated A clearance may
be reduced after TBI, thereby favoring amyloid deposition. It is
interesting that amyloid deposits were increased not unilaterally but
bilaterally after TBI in the presence of APOE4. This suggests that
mechanisms such as changes in APOE expression and
alterations in APOE-dependent clearance are likely to occur bilaterally
in this model of TBI.
The current study, in which the only known difference between the
groups of PDAPP mice was the presence or absence of human APOE
isoforms, provides evidence that isoform-specific APOE-A interactions contribute to the premature development of AD pathology. Although the promotion of amyloid deposition per se is unlikely to lead
to accelerated dementia, the neuritic dystrophy associated with amyloid
as well as other events coincident with or downstream of amyloid
formation in humans are likely to contribute to cognitive dysfunction.
These processes include A oligomer formation, tangle formation, cell
loss, and synaptic loss. Some in vivo studies have found
that apoE influences aspects of brain function and plasticity after
different forms of injury (Fagan et al., 1998; Sheng et al., 1998;
Stone et al., 1998; Buttini et al., 1999; Genis et al., 2000; Sabo et
al., 2000), including TBI (Chen et al., 1997), and it is possible that
APOE influences the outcome after different forms of brain injury via
more than one mechanism. Our data suggest that understanding the
mechanism(s) by which TBI promotes APOE isoform-dependent amyloid
deposition will lead to important insights into how accelerated
A-related AD-like changes occur and potential ways to prevent it.
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FOOTNOTES |
Received June 14, 2002; revised Sept. 5, 2002; accepted Sept. 18, 2002.
This work was supported by National Institutes of Health Grants
AG13956, AG05681, AG11355 (D.M.H.), DA07261 (R.E.H.), and NS08803; a
Veterans Administration Merit Review; and National Football League
Charities (T.K.M.)
Correspondence should be addressed to Dr. David M. Holtzman, Washington
University School of Medicine, Department of Neurology 660 South Euclid
Avenue, Box 8111, St. Louis, MO 63110. E-mail: holtzman{at}neuro.wustl.edu.
| |
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ABSTRACT
INTRODUCTION
