Traumatic brain injury (TBI) is a common
and often devastating health problem1,2.
Despite its prevalence, TBI has only recently
become widely recognized as a major health
issue — in part due to the intense media
attention on the high incidence of TBI in
ongoing military conflicts. In addition, there
has been a growing awareness of the
epidemiological association between a history
of TBI and the development of Alzheimer’s
disease (AD) later in life3–12. This link is
supported by the identification of acute and
chronic AD‑like pathologies in the brains of
TBI patients and in animal models of TBI.
There are several possible mechanisms
linking an episode of TBI to later develop‑
ment of neurodegenerative disease, such
as neuronal loss13–15, persistent inflamma‑
tion16,17 and cytoskeletal pathology18,19.
However, the pathophysiological link that
has received the most attention is the pro‑
duction, accumulation and clearance of
amyloid‑β (Aβ) peptides following TBI.
Here, we will examine the current under‑
standing of how a single TBI can trigger
both rapid and insidiously progressive
AD‑like pathological changes. In particular,
we will examine the association between
TBI and Aβ turnover.
TBI and AD: epidemiological link
Compelling data from several studies
demonstrate that a history of TBI is one
of the strongest epigenetic risk factors for
AD3–12,20. However, there is not a complete
consensus, as some epidemiological studies
have failed to find such an association21–28.
A major point of contention has been the
retrospective nature of some reports that
may have led to recall bias — a system‑
atic error due to inaccuracies in subjects’
ability to recall their history of TBI. This
is of particular concern when gathering
information from patients with cognitive
impairments or from secondary inform‑
ants. Nevertheless, larger, more control‑
led studies, including level 1 evidence
(which requires prospective examination
and randomization)11, has led to a general
acceptance that TBI is a risk factor for
It has also been suggested that a history
of TBI accelerates the onset of AD10,30–32,
and that the more severe the injury, the
greater the risk of developing AD9,11. Indeed,
because TBI is a complex and heterogene‑
ous disorder, the type and extent of the
acute pathology probably has an important
role in determining the risk of developing
AD. In addition, the baseline susceptibility
of the patient may be predetermined by
multiple factors such as age, sex and the
interplay of several known or unknown
genetic factors. For example, there is evi‑
dence that genetic predisposition, as a result
of an apolipoprotein E (APOE) polymor‑
phism, may influence the likelihood of
developing AD after TBI (BOX 1).
TBI and AD: pathological links
Human TBI and Aβ plaques. The first
clue indicating a pathological link between
TBI with AD was the observation that Aβ
plaques, a hallmark of AD33, are found in
up to 30% of patients who die acutely fol‑
lowing TBI34,35. Notably, these plaques were
found in all age groups, even in children.
By comparison, in control cases (individuals
that died from non‑neurological causes),
plaques were found almost exclusively in
elderly individuals35. Plaques have even
been observed in peri‑contusional tissue
surgically excised from survivors of TBI36,37.
The plaques found in TBI patients are
strikingly similar to those observed in
the early stages of AD (FIG. 1). However,
plaques in AD develop slowly and are pre‑
dominantly found in the elderly, whereas
TBI‑associated plaques can appear rapidly
(within just a few hours) after injury35,36.
In addition, plaques were identified fol‑
lowing a range of traumatically induced
pathologies that resulted from various
causes of injury35.
While TBI‑associated plaques largely
appear in the grey matter, they have also
been identified in white matter38. The pre‑
dominant type of Aβ peptide in the plaques
formed after TBI, and in the soluble Aβ
found in the brains of these patients, is
Aβ42, the AD‑associated form of Aβ that
is prone to aggregation37,39. Although the
plaques observed following trauma are typ‑
ically diffuse40, like those observed in early
AD, it is not known whether these plaques
mature over time into the denser, neuritic
plaques typical of advanced AD.
Although the existence of Aβ plaques
following trauma in humans is generally
well established34–36,38,41–43, it is only in recent
years that the mechanisms driving plaque
development have begun to be elucidated.
Human TBI and unaggregated Aβ peptides.
In contrast to the well‑characterized forma‑
tion of Aβ plaques after TBI, comparatively
little is known about how total brain con‑
centrations of Aβ, including both soluble
and oligomeric forms of the peptide, vary
An initial study reported an increase in
the presence of Aβ in ventricular cerebro‑
spinal fluid (CSF) following severe head
trauma44, although it is important to note
that control cases in this study were elderly,
which makes interpretation of these find‑
ings difficult. Levels of Aβ were elevated for
the first week after TBI and then declined
towards control levels in the subsequent
2 weeks44. In addition, the same Aβ peptide
that is predominant in plaques following
TBI, Aβ42, was found in the CSF of these
patients39,44,45. By contrast, a later study
reported a persistent decrease in Aβ con‑
centration in ventricular CSF from days 1–5
Traumatic brain injury and
amyloid‑β pathology: a link to
Victoria E. Johnson, William Stewart and Douglas H. Smith
Abstract | Traumatic brain injury (TBI) has devastating acute effects and in many
cases seems to initiate long-term neurodegeneration. Indeed, an epidemiological
association between TBI and the development of Alzheimer’s disease (AD) later in
life has been demonstrated, and it has been shown that amyloid-β (Aβ) plaques
— one of the hallmarks of AD — may be found in patients within hours following
TBI. Here, we explore the mechanistic underpinnings of the link between TBI and
AD, focusing on the hypothesis that rapid Aβ plaque formation may result from the
accumulation of amyloid precursor protein in damaged axons and a disturbed
balance between Aβ genesis and catabolism following TBI.
NATurE rEvIEWS | NeuroscieNce
voLumE 11 | mAy 2010 | 361
© 20 Macmillan Publishers Limited. All rights reserved10
following severe TBI46. This contradictory
finding was supported by a further study47,
although in this case progression over time
was not investigated and the collection time
points ranged from an acute measurement to
more than 9 months after injury. A further
caveat of this work was that the ventricular
CSF from TBI cases was compared with
lumbar CSF in controls47. Clearly there is a
lack of consensus on this issue. What influ‑
ences the movement of Aβ from the extra‑
cellular space to cerebrospinal circulation is
also unknown, particularly following TBI
in which blood–brain barrier permeability
and vascular integrity may be dramatically
altered. Therefore, it is not apparent whether
Aβ in CSF, either ventricular or lumbar,
reflects Aβ concentrations in the interstitial
space within the brain parenchyma.
recent studies have used invasive
intracranial microdialysis to obtain direct
measurements of brain parenchymal Aβ
concentrations in humans following severe
TBI48,49. Although no baseline (pre‑injury)
data were available, one such study found
that microdialysate Aβ concentrations
steadily increased over time following TBI,
and were correlated with improved global
neurological status48. one interpretation of
this finding is that depressed neuronal func‑
tion following TBI decreases Aβ genesis,
which subsequently returns to baseline as
recovery ensues. Another study that used
similar techniques failed to demonstrate any
overt change in post‑TBI Aβ concentrations
between 27 h and 99 h after TBI49. However,
they did find that patients with diffuse
axonal injury (DAI) had elevated Aβ levels
when compared with those with focal inju‑
ries, suggesting that the type of injury may
be an important influence on Aβ dynamics.
Axonal pathology: a source of Aβ?
Axonal injury after TBI. Although it is
likely that multiple sources contribute to Aβ
plaque formation after TBI, axonal swellings
represented an obvious pathology for exami‑
nation in initial investigations. Notably, DAI
is one of the most common pathologies of
TBI, and independently contributes to sig‑
nificant morbidity and mortality50–52. A key
feature of DAI is interruption of axonal
transport due to cytoskeletal disruption.
This causes an accumulation of proteins
in the axon, including amyloid precursor
protein (APP), which can be cleaved to
form Aβ53–57. These accumulations occur in
tortuous varicosities along the length of the
axon or at the disconnected axon terminals,
known as axonal bulbs. Although originally
described as diffuse, the actual distribu‑
tion of axonal pathology is multifocal, with
varicosities and bulbs occurring through‑
out the deep and subcortical white matter.
Swollen axons are particularly common in
midline structures such as the corpus cal‑
losum58. Eventual structural disorganization
of the axon can lead to secondary axonal
disconnection, which ultimately culmi‑
nates in a progressive, degenerative axonal
owing to the rapid and abundant
accumulation of APP in damaged axons
after TBI, APP immunostaining is used
for the pathological assessment of DAI in
humans53–58 (FIG. 1). Accordingly, it was sus‑
pected that this large reservoir of APP in
injured axons might be aberrantly cleaved
to rapidly form Aβ.
Acute Aβ formation in rodent TBI models.
Following the observation of acute Aβ
plaque formation in humans, and specula‑
tion that the source of Aβ may be damaged
axons, attention was turned to animal mod‑
els of TBI to explore this process (TaBle 1).
Studies using non‑transgenic rat models of
TBI investigated these pathologies in the
acute phase following injury62,63. However,
although these studies consistently found
extensive intra‑axonal accumulation of APP,
they failed to identify Aβ, via staining, in
either plaques or axons62,63.
The lack of evidence of Aβ deposition in
non‑transgenic rats was attributed, in part,
to differences in the Aβ peptides found in
different species. Accordingly, various trans‑
genic TBI models were utilized in an attempt
to replicate plaque pathology. Strains of
mice were selected for their predisposition
to the eventual development of Aβ plaques
with ageing. In a study using mice that
overexpress normal human APP, there was
an increase in tissue concentrations of Aβ40
acutely after injury. However, there was no
increase in plaque formation, overall pathol‑
ogy or altered functional outcome64. Further
studies used PDAPP mice, which overex‑
press a mutant form of APP and develop
Aβ plaque pathology as they age. TBI before
plaque formation induced a surge in the tis‑
sue concentration of Aβ that was associated
with an increase in hippocampal neuronal
death and memory impairment, indicat‑
ing the potential toxicity of Aβ65. However,
even in these mice, TBI did not induce acute
plaque formation. Furthermore, there was
a paradoxical reduction of plaques in the
PDAPP mice 8 months after TBI66. A similar
reduction in plaques was seen when aged
mice were subjected to injury, suggesting
that regression of plaques is possible67. It was
thought that the loss of hippocampal neurons
after injury actually decreased the over‑
all capacity to generate Aβ. Alternatively,
trauma may have induced a surge in Aβ
concentrations, which in turn upregulated
the mechanisms by which Aβ is cleared.
Acute elevations of hippocampal Aβ lev‑
els in the absence of plaques were also found
following injury in APPNLh/NLh
have both the Swedish familial AD mutation
and the human Aβ sequence knocked in
to their endogenous APP gene68,69. of note,
unlike the PDAPP mice, APP expression
Box 1 | The effects of apolipoprotein E genotype in traumatic brain injury
As with Alzheimer’s disease (AD)137,138, the lipid transport protein apolipoprotein E (APOE) has
been implicated in influencing amyloid pathology and outcome following traumatic brain injury
(TBI). A series of studies have found that individuals carrying the APOE ε4 allele were more likely
to have a poor outcome following injury139–147. However, there have also been reports that failed to
show any association between APOE ε4 carriers and outcome148–150. Indeed, a recent prospective
study examining 984 cases only found an association with possession of an APOE ε4 allele and
outcome in younger adults and children, with the association being strongest in patients aged less
than 15 years150. Thus, despite a general acceptance that possession of an APOE ε4 allele worsens
outcome after TBI, there is renewed debate in this regard.
Epidemiological data have provided additional information by implicating APOE4 genotype as a
risk factor for the later development of AD following TBI7,9,11,25,151–153. However, considerable debate
remains over whether APOE and TBI operate in a synergistic manner to increase the risk of AD
development or, alternatively, act as independent but additive risk factors.
Carriers of the APOE ε4 allele were found to be at increased risk of amyloid-β (Aβ) deposition
following TBI154. Aβ deposition was also significantly increased following head trauma in PDAPP
(platelet-derived growth factor promoter expressing amyloid precursor protein) mice carrying the
human APOE ε4 allele versus those carrying APOE ε3 or no APOE155. The mechanism by which
APOE is able to exert an effect on Aβ deposition remains elusive. In addition, the interplay of APOE
polymorphism with the microsatellite polymorphism in neprilysin, also shown to contribute to
Aβ deposition112, will be of interest. Indeed, when combined, these polymorphisms could
potentially provide useful predictive information.
362 | mAy 2010 | voLumE 11
© 20 Macmillan Publishers Limited. All rights reserved10
Nature Reviews | Neuroscience
in this model is dependant on the endog‑
enous promoter and thus continuous over‑
expression of APP does not occur. using
this model, it was demonstrated that, by
inhibiting caspase‑3 activity, injury‑induced
elevations in Aβ levels could be reduced in
association with improved histological out‑
comes68. In addition to providing a potential
mechanism of Aβ formation (see below),
this study further supported the idea that
post‑TBI increases in Aβ concentrations
without plaque formation may be detri‑
mental. Similarly, mice deficient in the rate‑
limiting enzyme for Aβ genesis — β‑amyloid
converting enzyme (BACE) — were found
to have significantly improved histological,
radiological and behavioural outcomes
Together, these data provide important
information regarding the potentially
harmful consequences of elevated Aβ levels
following TBI. However, they also con‑
sistently demonstrate that rodents fail to
recapitulate the plaque pathology observed
acutely following human TBI.
Acute Aβ formation in a swine TBI model.
Why rodent TBI models failed to recapitulate
the Aβ plaque pathology found acutely after
human TBI was a puzzle. Initially it was
thought that differences in the Aβ sequence
in rodents might prevent its aggregation into
plaques. However, even mice modified
to generate the human Aβ sequence failed to
develop plaques. It was therefore suggested
that Aβ production and deposition after
TBI may depend on brain anatomy as well
as the type of injury. Notably, rodents have
relatively small lissencephalic brains in
which white matter is sparse, meaning that
only limited axonal pathology can be pro‑
duced in rodent TBI models. Furthermore,
most rodent models utilize impact forces
to induce TBI, whereas a common cause of
human DAI is rotational acceleration, such
as occurs in automobile crashes.
Therefore, to more closely examine the
role of DAI on Aβ generation and deposi‑
tion, a swine model of head rotational
acceleration was used. This animal species
was selected because of its relatively large
gyrencephalic brain with extensive white
matter. Notably, the swine Aβ sequence is
identical to that of humans. This model
produces DAI that is very similar in appear‑
ance to that found clinically71,72. In addition
to the anticipated accumulation of APP
in swollen axons, co‑accumulation of Aβ
was also found18. Furthermore, this model
also induced the formation of parenchymal
Aβ diffuse plaques in both grey and white
matter. Although the number of plaques
was small compared to those found in
human TBI, this model finally enabled Aβ
deposition to be induced in an experimental
model. Furthermore, the co‑accumulation of
Aβ and APP in swollen axons hinted that the
potential mechanism of Aβ production after
TBI is linked to traumatic axonal injury.
Persistence of Aβ formation after TBI.
Following the identification and axonal
accumulation of Aβ plaques in the swine
TBI model, rodent TBI models were
re‑examined both acutely and with an
expanded time frame. Initially, Aβ accu‑
mulation was identified in damaged axons
shortly after injury in a rat model of TBI,
albeit still in the absence of Aβ plaques73.
Although there was concern about the
potential cross‑reactivity of the primary
Aβ antibody with APP in this study, another
study using a different rat model of TBI
used multiple specific antibodies to confirm
the axonal accumulation of Aβ74. However,
in this case only limited axonal Aβ was
found acutely, whereas greater axonal accu‑
mulations were found 1 month after injury
and persisted for at least 1 year. Increased
Aβ presence could also be seen within the
neuronal somata of these animals74. Notably,
these chronic increases in Aβ levels were
not associated with increased expression of
APP and no plaque formation was found at
any post‑injury time point74. These findings
clearly indicated the potentially chronic
nature of the trauma response with ongo‑
ing development of axonal pathology and
accompanying Aβ accumulation.
Interestingly, when the swine model
of head rotational acceleration injury was
examined up to 6 months after injury,
evidence of ongoing axonal pathology was
also revealed75. Again, this was character‑
ized by APP accumulation, often with
Figure 1 | immunohistochemical findings exploring mechanisms of amyloid‑β plaque formation
following traumatic brain injury. A | Representative amyloid-β (Aβ) plaques (brown) found acutely
following a single incidence of traumatic brain injury (TBI) caused by a fall in an 18 year old male. The
survival time from injury was just 10 hours. Plaques were identified using an antibody specific for Aβ.
B | Representative immunohistochemistry showing amyloid precursor protein (APP) (Ba), β-site-APP-
cleaving enzyme (BACE) (Bb) and presenilin-1(PS-1) (Bc) co-accumulating (Bd) in the disconnected
terminal of an axon, known as an axon bulb. c | Demonstration of axonal pathology using APP immuno-
histochemistry. APP (brown) accumulates within the tortuous varicosities along the length of damaged
axons. D | Increased neprilysin immunoreactivity (brown) is also observed in damaged axons following
TBI. Panel B is reproduced, with permission, from ReF. 42 © (2009) International Society of
NATurE rEvIEWS | NeuroscieNce
voLumE 11 | mAy 2010 | 363
© 20 Macmillan Publishers Limited. All rights reserved 10
co‑accumulation of Aβ. Although it was
generally thought that axonal pathol‑
ogy is only observed in the acute phase of
injury and is cleared within a few months
of trauma, these results demonstrated that
axonal degeneration may chronically per‑
sist42,74,75. moreover, the continued presence
of damaged axons offers a potential mecha‑
nism by which Aβ is chronically generated.
However, despite this long‑term produc‑
tion of Aβ, the quantity of Aβ plaques in
the tissue observed at 6 months following
trauma in swine had not increased
compared to that observed following
Axon pathology and Aβ in humans.
Examination of human brains also con‑
firmed the accumulation of Aβ in swollen
axons shortly after TBI38. more recently,
long‑term progressive axonal degenera‑
tion and intra‑axonal Aβ accumulation
was also identified following human TBI,
and persisted for years following the initial
trauma42. These findings demonstrate that
TBI can trigger long‑term neurodegen‑
erative processes in humans. This process
may account for the progressive selective
atrophy of white matter found after TBI
in humans76. However, the mechanisms
governing this protracted disconnection
and degeneration of axons are unknown.
It is possible that injured axons that do not
Table 1 | Animal models of traumatic brain injury and amyloid pathology
summary of findings
• No difference in neuronal loss, cognition or motor function following injury versus
• Decrease in total tissue levels of Aβ40 but not Aβ42 after injury
• Suppression of injury-induced elevations in caspase-3 by administration of a pan-caspase inhibitor
• Both caspase-cleaved APP and Aβ were reduced in association with improved histological outcome
Mouse (APPNLh/NLh) Controlled
Mouse (APPNLh/NLh) Controlled
• Administration of simvistatin 3 h after injury resulted in decreased hippocampal Aβ levels,
decreased hippocampal tissue loss and preserved synaptic integrity
• Behavioural outcome also improved
• Improved histological, radiological, behavioural and motor outcomes following injury versus
• Administration of a γ-secretase inhibitor (DAPT) in non-transgenic mice also improved outcomes
Mouse (PDAPP) Controlled
at 4 months old
• Levels of Aβ40 and Aβ42 in tissues increased following injury, peaking at 2 h
• Associated with increased hippocampal neuronal death and memory impairment
• No Aβ plaques were observed up to 2 months after injury
Mouse (PDAPP) Controlled
at 4 months old
• Decrease in Aβ plaques at 5 and 8 months after injury versus uninjured PDAPP mice (who normally
demonstrate abundant Aβ plaques at these time points)
at 2 years old
• Regression in Aβ plaque burden observed in the ipsilateral hippocampus of injured PDAPP mice
16 weeks after injury versus the contralateral hippocampus or uninjured PDAPP control mice
or apoe4, or
• PDAPP mice expressing apoe4 had increased Aβ deposition compared with those expressing apoe3
• Both groups displayed deposition at an age at which it is not observed in uninjured controls
• Mice with apoe4 demonstrated Aβ deposition that stained positive for thiaflavin-S in the molecular
layer of the dentate gyrus
• Extensive APP accumulation in damaged axons (1, 3 and 21 days following injury), and later in
• No accumulating Aβ observed intracellularly or in plaques
• APP accumulation in damaged axons up to 2 weeks following injury
• No Aβ observed at any time point intracellulary or in plaques
• Axonal accumulation of APP observed from 6 h to 10 days following trauma
• Aβ identified in damaged axons 12 h after injury
• Although APP and Aβ were persistently found in axons for up to 10 days after injury,
immunoreactivity reduced over time
• No plaques observed at any time
• Low levels of Aβ accumulated in axons, emerging at around 2 weeks after injury
• More profound immunoreactivity demonstrated at 1 month and persisted up to 1 year
• Extent of Aβ production was dependent on the maturity of the injury, but was uncoupled from the
gene expression of app
(model of DAI)
• Accumulation of intra-axonal APP and Aβ observed 3–10 days following injury
• Sparse, diffuse Aβ plaques observed in the grey and white matter over the same time course
• First animal model to replicate human Aβ plaque pathology observed after traumatic brain injury
(model of DAI)
• Aβ observed in axons, co-accumulating with APP, BACE and presenilin-1
• This was observed acutely (3 days and persisted up to 6 months after injury)
• Sparse Aβ plaques were observed both acutely and at 6 months following injury, but did not
increase in number over this time
Aβ, amyloid-β; APP, amyloid precursor protein; Bace, β-site APP-cleaving enzyme; DAI, diffuse axonal injury; DAPT, N-[(3,5-difluorophenyl)acetyl]-l-alanyl-2-phenyl]
glycin e-1,1-dimethylethyl ester; PDAPP, platelet-derived growth factor promoter expressing amyloid precursor protein; YAC, yeast artificial chromosome.
364 | mAy 2010 | voLumE 11
© 20 Macmillan Publishers Limited. All rights reserved10
Nature Reviews | Neuroscience
Disruption of axonal
transport leading to
axonal bulb formation
APP, BACE and PS-1
in axonal bulb
Intra-axonal Aβ formation
into Aβ plaques
Intra-axonal Aβ accumulation
Lysis and Aβ
degenerate in the acute phase are none‑
theless prone to later degeneration with a
secondary mild insult.
Aβ genesis and plaque formation in TBI.
Immunohistochemical analyses revealed
that the enzymes necessary for Aβ cleav‑
age also accumulate in injured axons after
TBI. Both presenilin‑1 (PS‑1) and BACE
were found in swollen axons in the swine
model of DAI75 and in humans42,43 (FIG. 1).
It seems that trauma creates a unique situ‑
ation whereby all the necessary substrates
for Aβ formation are forced to coexist in
the same place at the same time. It has been
postulated that the eventual lysis and break‑
down of these damaged axons may allow the
expulsion of Aβ into the parenchyma where
it aggregates to cause plaque formation18,75
(FIG. 2). Interestingly, at a much slower pace,
this general process of axonal transport fail‑
ure has been implicated as a mechanism of
plaque formation in AD77.
Although there is strong evidence to
support the idea that axons are a source of
post‑traumatic Aβ, it remains unknown why
plaque formation is more prevalent in the
grey matter following TBI. It is clear from
the multiple studies discussed above that
Aβ is not only present in white matter, but
may undergo a post‑TBI surge at these sites.
In addition, increased soluble Aβ has been
found in CSF following injury. Nevertheless,
there seems to be a predilection for grey mat‑
ter deposition, which also seems to be the
case in AD. There may be specific extracellu‑
lar attributes of the grey matter that selectively
promotes aggregation of Aβ into plaques.
Alternatively, it is possible that Aβ genesis
also occurs via a different mechanism in the
grey matter. observations of APP accumula‑
tion in synaptic terminals led to the sugges‑
tion that this may be another potential site of
Aβ genesis, leading to deposition in the grey
matter53. In addition, there may be multiple
mechanisms driving increased Aβ produc‑
tion following trauma at any location. It has
been postulated that elevated APP produc‑
tion in the neuronal soma following TBI may
saturate the normal α‑secretase processing
pathway, resulting in increased β‑secretase
processing and Aβ genesis53,78. Furthermore,
studies of hypoxia–ischaemia suggest that
Aβ genesis can be increased via oxidative‑
stress‑mediated upregulation of BACE79,80.
This BACE upregulation was later shown to
be mediated by γ‑secretase activity, which
was also enhanced due to oxidative stress81.
As oxidative stress is a well‑established con‑
sequence of TBI82, its role in promoting Aβ
genesis after injury warrants exploration.
Aβ dynamics in the various compart‑
ments, and their relative contributions to
plaque formation and pathogenicity, are
largely unknown. It is possible that TBI can
result in distinct Aβ dynamics as a result of
different mechanisms within the various
intracellular and extracellular compartments.
Elucidating these potential complexities in
neuronal Aβ dynamics will be an important
consideration for future studies.
Intra-axonal Aβ formation. Cleavage of
APP to form Aβ within the axonal mem‑
brane compartment is not consistent with
the classical description of Aβ genesis in
AD. As APP is a transmembrane protein,
it has long been assumed that amyloidogenic
processing results in the extracellular depo‑
sition of Aβ. However, increasing evidence
suggests that intracellular accumulation of
Aβ is possible and potentially pathogenic83.
recent studies have described Aβ pro‑
duction by BACE and PS‑1 in the axonal
membrane compartment of peripheral
nerves in mice84,85. The authors suggested
that APP, β‑secretase and PS‑1 are trans‑
ported within the axonal compartment
through a direct interaction between
kinesin‑1 and APP84,85. The observation of
Aβ within the axonal compartment led to
the suggestion that amyloidogenic cleav‑
age of APP can occur during transporta‑
tion84. However, these findings have been
directly challenged by another study that
failed to demonstrate co‑transportation of
either PS‑1 or BACE1 with APP in the same
murine peripheral nerve86. Furthermore,
they were unable to detect Aβ peptides
Figure 2 | Potential mechanisms of post‑traumatic amyloid‑β formation and clearance.
a | The mechanical forces that axons are subjected to during a traumatic event can damage axons by
directly altering their structure or by initiating detrimental secondary cascades. Failure of axonal trans-
port in these injured axons results in accumulation of multiple proteins that form swellings at their
disconnected terminals known as axon bulbs. b | Such protein accumulation has been demonstrated
to include the enzymes necessary for the cleavage of amyloid precursor protein (APP) to amyloid-β
(Aβ), including presenilin-1 (PS-1) and β-site APP-cleaving enzyme (BACE). c–d | Although the precise
intracellular mechanism of Aβ genesis remains unclear, lipid rafts have been suggested to be important
in allowing APP processing and thus Aβ accumulation within the axonal compartment. e–f | Injured
axons that go on to degenerate and lyse will expel the accumulated Aβ into the brain parenchyma
where it is at risk of aggregating into plaques. g | The enzyme that clears Aβ, neprilsyin (NEP), also
accumulates in damaged axons and probably mitigates the effects of enhanced Aβ production. The
balance of genesis versus catabolism will ultimately determine Aβ build-up. NEP may potentially act
to clear Aβ within the axonal compartment or in the extracellular space.
NATurE rEvIEWS | NeuroscieNce
voLumE 11 | mAy 2010 | 365
© 20 Macmillan Publishers Limited. All rights reserved10
within this nerve. The authors suggest that,
at least within the peripheral nervous sys‑
tem, intraxonal transport of the machinery
of Aβ genesis is unlikely. Whether this is
also true for the CNS is unknown.
Intra‑axonal processing of membrane‑
bound APP may involve lipid rafts —
cholesterol‑rich microdomains of the plasma
membrane that are thought to compartmen‑
talize cellular processes87, 88. Indeed, there is
evidence indicating that lipid rafts may be
important in amyloidogenic processing of
APP in neurons89. Axons are also abundant
with lipid‑rich invaginations of plasma
membrane known as caveolae, which may
provide another intra‑axonal site of APP
processing. It is possible that mechanical
damage to axons due to trauma may cause
changes in linear lipid rafts or caveolae that
promote abnormal APP processing. A recent
study using APPNLh/NLh
administration of the cholesterol‑lowering
drug simvastatin diminished increases in
Aβ levels following injury69. Associated
histological and behavioural outcomes were
also improved. Although the mechanisms by
which simvastatin modulates Aβ dynamics
may be complex, further exploration of
its possible role in post‑traumatic Aβ
processing will be of interest.
mice showed that
Caspases, TBI and Aβ processing.
proteases (caspases) have been identified
as important in Aβ genesis90. This finding
is of particular interest with regards to TBI,
in which increased caspase activation has
been described in humans and in animal
Following controlled cortical impact in
APP mice, pharmacological inhibition of
injury‑induced caspase‑3 activation using
a pan‑caspase inhibitor (Boc‑Asp(ome)‑
CH2F) reduced both caspase‑3‑mediated APP
processing and acute elevations in Aβ con‑
centrations68. In addition, there was decreased
neuron degeneration and tissue loss. A fur‑
ther study demonstrated caspase‑3‑mediated
APP proteolysis in traumatically injured
axons following head impact in a rat73.
Although the precise mechanisms by
which caspases act to increase Aβ levels
are not clear, recent work indicates that
caspase‑3 may increase APP processing by
increasing the availability of BACE via an
adaptor molecule (GGA3) that interrupts
BACE trafficking and prevents its degrada‑
tion95. Elevated BACE levels and activity
would promote amyloidogenic processing
of APP, potentially leading to increased
Aβ genesis. Interestingly, elevated BACE
levels and activity have been found following
injury in a rat model of TBI96.
This work highlights the need for better
understanding of the mechanisms of Aβ
genesis in the post‑trauma situation. Little
is known about how, or if, β‑secretase and
γ‑secretase activity are altered by trauma.
Furthermore, how this influences the role of
the non‑amyloidogenic α‑secretase pathway
is largely unknown.
Aβ catabolism in TBI
The observed variations in plaque pathol‑
ogy in humans and in animal models of TBI
provided valuable clues regarding potential
mechanisms of plaque genesis. They sug‑
gested that some species, and perhaps cer‑
tain individuals, are able to clear Aβ more
efficiently than others, potentially because
of differences in the extent or activity of
Aβ degrading mechanisms. This revelation
turned attention to potential mechanisms of
Aβ clearance after TBI.
Neprilysin, a membrane zinc metallo‑
endopeptidase, has emerged as a sig‑
nificant Aβ degrading enzyme in vivo97,98,
although there are others including insulin
degrading enzyme99. Neprilysin is trans‑
cribed in a tissue‑specific manner100,101,
operates as a transmembrane glycopro‑
tein102,103 and is capable of degrading mon‑
omeric and potentially oligomeric forms of
Aβ104. Furthermore, neprilysin knockout
mice have been shown to accumulate Aβ40
and Aβ42 in a gene dose‑dependant man‑
ner105. Neprilysin has been increasingly
implicated in the pathogenesis of AD106.
Indeed, patients with sporadic AD were
found to have up to a 50% reduction in
neprilysin mrNA in areas associated with
Neprilysin following human TBI. It has
recently been observed that immuno‑
reactivity to neprilysin increases for
many months following TBI in humans42.
Extensive neprilysin immunoreactivity was
found in the neuronal soma and axonal
bulbs of long‑term survivors of TBI (FIG. 1).
Interestingly, these cases comprised the
same group that have a virtual absence of
Aβ plaques. These findings suggest that
these individuals may have a long‑term
upregulation of neprilysin that continu‑
ally clears both intracellular and/or extra‑
cellular Aβ, thereby promoting plaque
regression. moreover, the findings suggest
that neprilysin may have an important
role in mitigating chronic Aβ produc‑
tion induced by trauma. Although the
site at which neprilysin acts to achieve
this has not been identified, the presence
of neprilysin within axons suggests that
intra‑axonal clearance is one possible
mechanism. However, it remains to be
determined whether neprilysin is able to
function extracellulary to clear plaques
directly or whether plaque turnover is
regulated by some other means.
Notably, microglia containing Aβ have
been found in association with plaques
after TBI42, suggesting that phagocytic
clearance of plaques may occur. It is pos‑
sible that the extent of the microglial
response following injury may influence
plaque burden. Like neprilysin, this could
potentially contribute to variations in
plaque pathology between individuals and
indeed animal species. In support of this
idea, recent work suggests that increased
microglial activation is the mechanism by
which passive Aβ immunization thera‑
pies act to clear plaques in AD models108.
Interestingly, microglia also appear to
utilize neprilysin to process Aβ109.
Neprilysin polymorphisms and Aβ plaques.
Neprilysin expression is probably regulated
by multiple mechanisms, including the
production of Aβ itself, which has been
suggested to trigger a positive‑feedback
loop110,111. Genetic variation may also influ‑
ence the extent of expression or activity of
neprilysin, which potentially accounts for
the presence of Aβ plaques in only 30% of
TBI patients. Indeed a recent study identi‑
fied a relationship between a neprilysin poly‑
morphism and Aβ plaque pathology acutely
following TBI112, although whether this
association is functionally significant or a
result of genetic linkage is unknown. Further
studies may be of value in determining how
this polymorphism affects both short‑term
and long‑term clinical outcome. As such, a
genetic screening test of this neprilysin poly‑
morphism could potentially help to identify
individuals at risk of plaque formation,
which may be an important consideration
for those involved in military action or
contact sports (BOX 2).
App and Aβ in TBI pathophysiology
It is unclear whether the accumulation
of large quantities of APP in damaged
axons after TBI serves a mechanistic role
or is simply an epiphenomenon. It has
been suggested that APP and its non‑
amyloidogenic processing have beneficial
effects with respect to neuroprotection,
neurite outgrowth and synaptogenesis113–120.
In addition, the administration of soluble
APPα (the product of non‑amyloidogenic
366 | mAy 2010 | voLumE 11
© 20 Macmillan Publishers Limited. All rights reserved10
processing via the α‑secretase pathway)
improved functional outcome and reduced
neuronal cell loss and axonal injury
following TBI in rats120.
The role of Aβ plaques in TBI outcome
has also not yet been established. Even in
AD, considerable debate remains over the
pathogenicity of Aβ plaques (as opposed to
its unaggregated soluble forms)121–123. Indeed,
a recent investigation in which apparent Aβ
plaque clearance followed Aβ immunization
in patients with AD failed to demonstrate
altered clinical outcome124. Furthermore,
recent evidence suggests that unaggregated
oligomeric forms of Aβ may contribute to
toxicity125–130. As such, rapid aggregation of
Aβ into plaques may be a protective event.
An evaluation of the role of oligomeric Aβ
following TBI will therefore be an
important future consideration. So far, only
one study has implicated unaggregated
Aβ toxicity in neuron death after TBI.
As described above, TBI in PDAPP mice
resulted in extensive hippocampal neuron
death and associated neurocognitive impair‑
ment in association with a local surge in
unaggregated Aβ levels in the hippocam‑
pus65. This may suggest that the toxic prop‑
erties of Aβ only emerge when levels exceed
a certain threshold131.
unaggregated Aβ could have other
deleterious effects in TBI. Solubilized Aβ
injected into the brains of rodents has pro‑
found effects on cognition and long‑term
potentiation — an electrophysiological
correlate of some forms of learning and
memory132–134. Thus, after TBI an acute
surge in Aβ concentrations, as well as its
continued production for years, may
influence functional recovery.
Conclusions and future directions
The link between trauma and the later
development of neurodegenerative dis‑
eases such as AD is likely to be extremely
complex, and work in this field remains
in its infancy. one recurring issue in this
field of research is the involvement of
axons and the pathological accumulation
of multiple proteins within axons damaged
by trauma. This parallels the increasing
emphasis on axonal involvement in the
pathogenesis of AD, particularly axonal
TBI is a common, devastating disor‑
der and is the leading cause of death in
children and young adults135. The later
development of AD or neurodegenerative
disease comes not only at a human cost,
but also constitutes a considerable socioe‑
conomic burden. Hence, this is an avenue
of research of potential importance to
almost everyone, and may have particular
significance to those at high risk of TBI,
such as those involved in contact sports
players or in the military.
A mechanistic understanding of what
drives the risk of developing AD following
TBI will be imperative for the develop‑
ment of post‑trauma interventions aimed
at halting the onslaught of such debilitat‑
ing neurodegeneration. Furthermore, the
advancement of drug discoveries in the
field of AD, such as BACE and γ‑secretase
inhibitors70,136 or neprilysin replacement
strategies, may have potentially important
roles in both the acute and chronic
management of TBI.
Victoria E. Johnson is at the Penn Center for
Brain Injury and Repair, Department
of Neurosurgery, University of Pennsylvania School of
Medicine, 3320 Smith Walk, Hayden Hall 105,
Philadelphia, Pennsylvania 19104, USA, and at the
University of Glasgow, University Avenue,
Glasgow G12 8QQ,UK.
William Stewart is at the Department
of Neuropathology, Southern General Hospital,
1345 Govan Road, Glasgow G51 4TF, UK, and at the
University of Glasgow.
Douglas H. Smith is at the Penn Center for
Brain Injury and Repair, Department
of Neurosurgery, University of Pennsylvania School
of Medicine, 3320 Smith Walk, Hayden Hall 105,
Philadelphia, Pennsylvania 19104, USA,
Correspondence to D.H.S.
Published online 10 March 2010
Langlois, J. A., Rutland‑Brown, W. & Thomas, K. E.
Traumatic Brain Injury in the United States: Emergency
Department Visits, Hospitalizations, and Deaths.
(Centers for Disease Control and Prevention, Nation
Center for Injury Prevention and Control, Atlanta,
Thurman, D., Alverson, C., Dunn, K., Guerrero, J. &
Sniezek, J. Traumatic brain injury in the United States:
a public health perspective. J. Head Trauma Rehabil.
14, 602–615 (1999).
Molgaard, C. A. et al. Epidemiology of head trauma
and neurocognitive impairment in a multi‑ethnic
population. Neuroepidemiology 9, 233–242 (1990).
Mortimer, J. A., French, L. R., Hutton, J. T. &
Schuman, L. M. Head injury as a risk factor for
Alzheimer’s disease. Neurology 35, 264–267
Mortimer, J. A. et al. Head trauma as a risk factor
for Alzheimer’s disease: a collaborative re‑analysis of
case–control studies. EURODEM Risk Factors
Research Group. Int. J. Epidemiol. 20 (Suppl. 2),
Graves, A. B. et al. The association between head
trauma and Alzheimer’s disease. Am. J. Epidemiol.
131, 491–501 (1990).
O’Meara, E. S. et al. Head injury and risk of
Alzheimer’s disease by apolipoprotein E genotype.
Am. J. Epidemiol. 146, 373–384 (1997).
Box 2 | Repetitive traumatic brain injury
In 1928, the term ‘punch drunk syndrome’ was introduced to describe a disorder of
progressive dementia that develops after repetitive traumatic brain injury (TBI) from
boxing156. Now termed ‘dementia pugilistica’157, this syndrome can present many years after
retiring from boxing158, affecting as many as 17% of retired boxers159. The incidence of
dementia pugilistica increases with duration of time spent boxing159, number of knockouts
experienced160 and apolipoprotein E (APOE) genotype161. Although this work has been centred
on boxers, increasing evidence suggests that repetitive TBI experienced from playing
professional American football can result in increased rates of late-life cognitive
impairment162. Furthermore, recent pathological studies of the brains of former players in the
National Football League in the United States of America revealed extensive Alzheimer’s
disease (AD)-like neurofibrillary tangles (NFTs) and, in some cases, amyloid-β (Aβ)
Although the predominant pathology of dementia pugilistica is the formation of AD-like
NFTs, Aβ pathologies later emerged as a potentially important finding. As with single TBI and
AD, diffuse Aβ plaques are found in the brain158,166. Deposits of Aβ have also been observed in
both leptomeningeal and cortical blood vessels166. More recently, accelerated Aβ deposition
was observed following a model of mild repetitive TBI in Tg2576 mice (known to develop Aβ
plaques with ageing)167,168. This increased deposition was found in association with evidence
of increased lipid peroxidation and could be reversed by pretreatment with oral vitamin E168.
NFTs and neuropil threads are an important feature of both AD and dementia
pugilistica19,158,165,169–173. These intracellular structures contain abnormal (hyperphosphor-
ylated) forms of the microtubule-associated protein tau. One study found NFTs and neuropil
threads in the neocortex of five cases of repetitive, mild head trauma in young patients19. In
addition, the molecular profile and ubiquitylation of tau in dementia pugilistica was similar to
that observed in the filamentous tau inclusions seen in AD173,174.
In contrast to well-developed tau pathology in dementia pugilistica, NFTs were not found to
be acutely increased after a single TBI175. Although tau has also been observed accumulating
in axons following trauma, this was only found in a small subset of patients36,43. In a study in
which pigs received single experimental brain injuries, accumulations of tau were observed in
a limited number of neuronal perikarya18. Rats also demonstrated phosphorylated tau
accumulation in neurons at 6 months after injury176.
NATurE rEvIEWS | NeuroscieNce
voLumE 11 | mAy 2010 | 367
© 20 Macmillan Publishers Limited. All rights reserved 10
Salib, E. & Hillier, V. Head injury and the risk of
Alzheimer’s disease: a case control study. Int.
J. Geriatr. Psychiatry 12, 363–368 (1997).
Guo, Z. et al. Head injury and the risk of AD in
the MIRAGE study. Neurology 54, 1316–1323
10. Schofield, P. W. et al. Alzheimer’s disease after remote
head injury: an incidence study. J. Neurol. Neurosurg.
Psychiatry 62, 119–124 (1997).
11. Plassman, B. L. et al. Documented head injury in early
adulthood and risk of Alzheimer’s disease and other
dementias. Neurology 55, 1158–1166 (2000).
12. Fleminger, S., Oliver, D. L., Lovestone, S.,
Rabe‑Hesketh, S. & Giora, A. Head injury as a risk
factor for Alzheimer’s disease: the evidence 10 years
on; a partial replication. J. Neurol. Neurosurg.
Psychiatry 74, 857–862 (2003).
13. Kotapka, M. J., Graham, D. I., Adams, J. H. &
Gennarelli, T. A. Hippocampal pathology in fatal
non‑missile human head injury. Acta Neuropathol.
83, 530–534 (1992).
14. Smith, D. H. et al. Progressive atrophy and neuron
death for one year following brain trauma in the rat.
J. Neurotrauma 14, 715–727 (1997).
15. Maxwell, W. L., Mackinnon, M. A., Stewart, J. E. &
Graham, D. I. Stereology of cerebral cortex after
traumatic brain injury matched to the Glasgow
Outcome Score. Brain 133,139–160 (2010).
16. Gentleman, S. M. et al. Long‑term intracerebral
inflammatory response after traumatic brain injury.
Forensic Sci. Int. 146, 97–104 (2004).
17. Nicoll, J. A. et al. Association of interleukin‑1 gene
polymorphisms with Alzheimer’s disease. Ann. Neurol.
47, 365–368 (2000).
18. Smith, D. H. et al. Accumulation of amyloid beta and
tau and the formation of neurofilament inclusions
following diffuse brain injury in the pig.
J. Neuropathol. Exp. Neurol. 58, 982–992 (1999).
19. Geddes, J. F., Vowles, G. H., Nicoll, J. A. &
Revesz, T. Neuronal cytoskeletal changes are
an early consequence of repetitive head injury.
Acta Neuropathol. 98, 171–178 (1999).
20. van Duijn, C. M. et al. Head trauma and the risk of
Alzheimer’s disease. Am. J. Epidemiol. 135, 775–782
21. Chandra, V., Philipose, V., Bell, P. A., Lazaroff, A. &
Schoenberg, B. S. Case–control study of late onset
“probable Alzheimer’s disease”. Neurology 37,
22. Amaducci, L. A. et al. Risk factors for clinically
diagnosed Alzheimer’s disease: a case–control study
of an Italian population. Neurology 36, 922–931
23. Broe, G. A. et al. A case–control study of Alzheimer’s
disease in Australia. Neurology 40, 1698–1707
24. Ferini‑Strambi, L., Smirne, S., Garancini, P., Pinto, P. &
Franceschi, M. Clinical and epidemiological aspects of
Alzheimer’s disease with presenile onset: a case
control study. Neuroepidemiology 9, 39–49 (1990).
25. Katzman, R. et al. Development of dementing illnesses
in an 80‑year‑old volunteer cohort. Ann. Neurol. 25,
26. Launer, L. J. et al. Rates and risk factors for dementia
and Alzheimer’s disease: results from EURODEM
pooled analyses. EURODEM Incidence Research
Group and Work Groups. European Studies of
Dementia. Neurology 52, 78–84 (1999).
27. Williams, D. B., Annegers, J. F., Kokmen, E.,
O’Brien, P. C. & Kurland, L. T. Brain injury and
neurologic sequelae: a cohort study of dementia,
parkinsonism, and amyotrophic lateral sclerosis.
Neurology 41, 1554–1557 (1991).
28. Mehta, K. M. et al. Head trauma and risk of dementia
and Alzheimer’s disease: the Rotterdam study.
Neurology 53, 1959–1962 (1999).
29. Lye, T. C. & Shores, E. A. Traumatic brain injury
as a risk factor for Alzheimer’s disease: a review.
Neuropsychol. Rev. 10, 115–129 (2000).
30. Sullivan, P., Petitti, D. & Barbaccia, J. Head trauma
and age of onset of dementia of the Alzheimer type.
JAMA 257, 2289–2290 (1987).
31. Gedye, A., Beattie, B. L., Tuokko, H., Horton, A. &
Korsarek, E. Severe head injury hastens age of
onset of Alzheimer’s disease. J. Am. Geriatr. Soc.
37, 970–973 (1989).
32. Nemetz, P. N. et al. Traumatic brain injury and time
to onset of Alzheimer’s disease: a population‑based
study. Am. J. Epidemiol. 149, 32–40 (1999).
33. Victor, M. R. & Ropper, A. H. Adams and Victor’s
Principles of Neurology 1–1692 (McGraw‑Hill, 2001).
34. Roberts, G. W., Gentleman, S. M., Lynch, A. &
Graham, D. I. βA4 amyloid protein deposition in
brain after head trauma. Lancet 338, 1422–1423
35. Roberts, G. W. et al. Beta amyloid protein deposition
in the brain after severe head injury: implications for
the pathogenesis of Alzheimer’s disease. J. Neurol.
Neurosurg. Psychiatry 57, 419–425 (1994).
36. Ikonomovic, M. D. et al. Alzheimer’s pathology in
human temporal cortex surgically excised after severe
brain injury. Exp. Neurol. 190, 192–203 (2004).
37. DeKosky, S. T. et al. Association of increased cortical
soluble Aβ42 levels with diffuse plaques after severe
brain injury in humans. Arch. Neurol. 64, 541–544
38. Smith, D. H., Chen, X. H., Iwata, A. & Graham, D. I.
Amyloid β accumulation in axons after traumatic
brain injury in humans. J. Neurosurg. 98, 1072–1077
39. Gentleman, S. M. et al. Aβ42 is the predominant
form of amyloid β‑protein in the brains of short‑term
survivors of head injury. Neuroreport 8, 1519–1522
40. Horsburgh, K. et al. β‑amyloid (Aβ)42(43), Aβ42,
Aβ40 and apoE immunostaining of plaques in
fatal head injury. Neuropathol. Appl. Neurobiol. 26,
41. Huber, A., Gabbert, K., Kelemen, J. &
Cervod‑Navarro, J. Density of amyloid plaques
in brains after head trauma. J. Neurotrauma 10
(Suppl. 1), 180 (1993).
42. Chen, X. H., Johnson, V. E., Uryu, K., Trojanowski, J. Q.
& Smith, D. H. A lack of amyloid β plaques despite
persistent accumulation of amyloid β in axons of long‑
term survivors of traumatic brain injury. Brain Pathol.
19, 214–223 (2009).
43. Uryu, K. et al. Multiple proteins implicated in
neurodegenerative diseases accumulate in axons after
brain trauma in humans. Exp. Neurol. 208, 185–192
44. Raby, C. A. et al. Traumatic brain injury increases
β‑amyloid peptide 1–42 in cerebrospinal fluid.
J. Neurochem. 71, 2505–2509 (1998).
45. Emmerling, M. R. et al. Traumatic brain injury elevates
the Alzheimer’s amyloid peptide Aβ42 in human CSF.
A possible role for nerve cell injury. Ann. NY Acad. Sci.
903, 118–122 (2000).
46. Kay, A. D. et al. Alterations in cerebrospinal fluid
apolipoprotein E and amyloid β‑protein after
traumatic brain injury. J. Neurotrauma 20, 943–952
47. Franz, G. et al. Amyloid β 1–42 and tau in
cerebrospinal fluid after severe traumatic brain injury.
Neurology 60, 1457–1461 (2003).
48. Brody, D. L. et al. Amyloid‑β dynamics correlate
with neurological status in the injured human brain.
Science 321, 1221–1224 (2008).
49. Marklund, N. et al. Monitoring of brain interstitial
total tau and β amyloid proteins by microdialysis in
patients with traumatic brain injury. J. Neurosurg.
110, 1227–1237 (2009).
50. Geddes, J. F., Vowles, G. H., Beer, T. W. & Ellison, D. W.
The diagnosis of diffuse axonal injury: implications
for forensic practice. Neuropathol. Appl. Neurobiol.
23, 339–347 (1997).
51. Geddes, J. F., Whitwell, H. L. & Graham, D. I.
Traumatic axonal injury: practical issues for diagnosis
in medicolegal cases. Neuropathol. Appl. Neurobiol.
26, 105–116 (2000).
52. Adams, J. H., Graham, D. I., Murray, L. S. & Scott, G.
Diffuse axonal injury due to nonmissile head injury
in humans: an analysis of 45 cases. Ann. Neurol. 12,
53. Gentleman, S. M., Nash, M. J., Sweeting, C. J.,
Graham, D. I. & Roberts, G. W. Beta‑amyloid
precursor protein (beta APP) as a marker for axonal
injury after head injury. Neurosci. Lett. 160, 139–144
54. Gorrie, C., Oakes, S., Duflou, J., Blumbergs, P. &
Waite, P. M. Axonal injury in children after motor
vehicle crashes: extent, distribution, and size of
axonal swellings using β‑APP immunohistochemistry.
J. Neurotrauma 19, 1171–1182 (2002).
55. Sherriff, F. E., Bridges, L. R. & Sivaloganathan, S. Early
detection of axonal injury after human head trauma
using immunocytochemistry for beta‑amyloid precursor
protein. Acta Neuropathol. 87, 55–62 (1994).
56. Lambri, M., Djurovic, V., Kibble, M., Cairns, N. &
Al‑Sarraj, S. Specificity and sensitivity of βAPP in
head injury. Clin. Neuropathol. 20, 263–271
57. Reichard, R. R., White, C. L. 3rd, Hladik, C. L. &
Dolinak, D. Beta‑amyloid precursor protein staining of
nonaccidental central nervous system injury in pediatric
autopsies. J. Neurotrauma 20, 347–355 (2003).
58. Adams, J. H. et al. Diffuse axonal injury in head injury:
definition, diagnosis and grading. Histopathology 15,
59. Povlishock, J. T. & Becker, D. P. Fate of reactive axonal
swellings induced by head injury. Lab. Invest. 52,
60. Maxwell, W. L., Povlishock, J. T. & Graham, D. L. A
mechanistic analysis of nondisruptive axonal injury:
a review. J. Neurotrauma 14, 419–440 (1997).
61. Maxwell, W. L., Domleo, A., McColl, G., Jafari, S. S. &
Graham, D. I. Post‑acute alterations in the axonal
cytoskeleton after traumatic axonal injury.
J. Neurotrauma 20, 151–168 (2003).
62. Lewen, A., Li, G. L., Nilsson, P., Olsson, Y. &
Hillered, L. Traumatic brain injury in rat
produces changes of β‑amyloid precursor protein
immunoreactivity. Neuroreport 6, 357–360 (1995).
63. Pierce, J. E., Trojanowski, J. Q., Graham, D. I.,
Smith, D. H. & McIntosh, T. K. Immunohistochemical
characterization of alterations in the distribution of
amyloid precursor proteins and β‑amyloid peptide
after experimental brain injury in the rat. J. Neurosci.
16, 1083–1090 (1996).
64. Murai, H. et al. Twofold overexpression of human
β‑amyloid precursor proteins in transgenic mice does
not affect the neuromotor, cognitive, or
neurodegenerative sequelae following experimental
brain injury. J. Comp. Neurol. 392, 428–438
65. Smith, D. H. et al. Brain trauma induces massive
hippocampal neuron death linked to a surge in
β‑amyloid levels in mice overexpressing mutant
amyloid precursor protein. Am. J. Pathol. 153,
66. Nakagawa, Y. et al. Traumatic brain injury in young,
amyloid‑β peptide overexpressing transgenic mice
induces marked ipsilateral hippocampal atrophy
and diminished Aβ deposition during aging. J. Comp.
Neurol. 411, 390–398 (1999).
67. Nakagawa, Y. et al. Brain trauma in aged transgenic
mice induces regression of established Aβ deposits.
Exp. Neurol. 163, 244–252 (2000).
68. Abrahamson, E. E. et al. Caspase inhibition therapy
abolishes brain trauma‑induced increases in Aβ
peptide: implications for clinical outcome. Exp. Neurol.
197, 437–450 (2006).
69. Abrahamson, E. E., Ikonomovic, M. D., Dixon, C. E. &
DeKosky, S. T. Simvastatin therapy prevents brain
trauma‑induced increases in β‑amyloid peptide levels.
Ann. Neurol. 66, 407–414 (2009).
70. Loane, D. J. et al. Amyloid precursor protein
secretases as therapeutic targets for traumatic
brain injury. Nature Med. 15, 377–379 (2009).
71. Smith, D. H. et al. Characterization of diffuse axonal
pathology and selective hippocampal damage
following inertial brain trauma in the pig.
J. Neuropathol. Exp. Neurol. 56, 822–834 (1997).
72. Meaney, D. F. et al. Biomechanical analysis of
experimental diffuse axonal injury. J. Neurotrauma
12, 689–694 (1995).
73. Stone, J. R. et al. Caspase‑3‑mediated cleavage of
amyloid precursor protein and formation of amyloid β
peptide in traumatic axonal injury. J. Neurotrauma
19, 601–614 (2002).
74. Iwata, A., Chen, X. H., McIntosh, T. K., Browne, K. D. &
Smith, D. H. Long‑term accumulation of amyloid‑β in
axons following brain trauma without persistent
upregulation of amyloid precursor protein genes.
J. Neuropathol. Exp. Neurol. 61, 1056–1068 (2002).
75. Chen, X. H. et al. Long‑term accumulation of
amyloid‑β, β‑secretase, presenilin‑1, and caspase‑3 in
damaged axons following brain trauma. Am. J. Pathol.
165, 357–371 (2004).
76. Bigler, E. D. Quantitative magnetic resonance imaging
in traumatic brain injury. J. Head Trauma Rehabil. 16,
77. Stokin, G. B. et al. Axonopathy and transport deficits
early in the pathogenesis of Alzheimer’s disease.
Science 307, 1282–1288 (2005).
78. Graham, D. I. et al. Altered β‑APP metabolism after
head injury and its relationship to the aetiology of
Alzheimer’s disease. Acta Neurochir. Suppl. 66,
79. Tamagno, E. et al. β‑Site APP cleaving enzyme
up‑regulation induced by 4‑hydroxynonenal is
mediated by stress‑activated protein kinases
pathways. J. Neurochem. 92, 628–636 (2005).
368 | mAy 2010 | voLumE 11
© 20 Macmillan Publishers Limited. All rights reserved10
80. Guglielmotto, M. et al. The up‑regulation of BACE1
mediated by hypoxia and ischemic injury: role of
oxidative stress and HIF1α. J. Neurochem. 108,
81. Tamagno, E. et al. Oxidative stress activates a positive
feedback between the γ‑ and β‑secretase cleavages of
the β‑amyloid precursor protein. J. Neurochem. 104,
82. Povlishock, J. T. & Kontos, H. A. The role of oxygen
radicals in the pathobiology of traumatic brain injury.
Hum. Cell 5, 345–353 (1992).
83. LaFerla, F. M., Green, K. N. & Oddo, S. Intracellular
amyloid‑β in Alzheimer’s disease. Nature Rev.
Neurosci. 8, 499–509 (2007).
84. Kamal, A., Almenar‑Queralt, A., LeBlanc, J. F.,
Roberts, E. A. & Goldstein, L. S. Kinesin‑mediated
axonal transport of a membrane compartment
containing β‑secretase and presenilin‑1 requires APP.
Nature 414, 643–648 (2001).
85. Kamal, A., Stokin, G. B., Yang, Z., Xia, C. H. &
Goldstein, L. S. Axonal transport of amyloid precursor
protein is mediated by direct binding to the kinesin
light chain subunit of kinesin‑I. Neuron 28, 449–459
86. Lazarov, O. et al. Axonal transport, amyloid precursor
protein, kinesin‑1, and the processing apparatus:
revisited. J. Neurosci. 25, 2386–2395 (2005).
87. Simons, K. & Toomre, D. Lipid rafts and signal
transduction. Nature Rev. Mol. Cell Biol. 1, 31–39
88. Pike, L. J. Rafts defined: a report on the Keystone
symposium on lipid rafts and cell function. J. Lipid Res.
47, 1597–1598 (2006).
89. Ehehalt, R., Keller, P., Haass, C., Thiele, C. &
Simons, K. Amyloidogenic processing of the Alzheimer
β‑amyloid precursor protein depends on lipid rafts.
J. Cell Biol. 160, 113–123 (2003).
90. Gervais, F. G. et al. Involvement of caspases in
proteolytic cleavage of Alzheimer’s amyloid‑β
precursor protein and amyloidogenic Aβ peptide
formation. Cell 97, 395–406 (1999).
91. Clark, R. S. et al. Increases in Bcl‑2 and cleavage of
caspase‑1 and caspase‑3 in human brain after head
injury. FASEB J. 13, 813–821 (1999).
92. Knoblach, S. M. et al. Multiple caspases are
activated after traumatic brain injury: evidence for
involvement in functional outcome. J. Neurotrauma
19, 1155–1170 (2002).
93. Yakovlev, A. G. et al. Activation of CPP32‑like caspases
contributes to neuronal apoptosis and neurological
dysfunction after traumatic brain injury. J. Neurosci.
17, 7415–7424 (1997).
94. Sanchez Mejia, R. O., Ona, V. O., Li, M. &
Friedlander, R. M. Minocycline reduces traumatic
brain injury‑mediated caspase‑1 activation, tissue
damage, and neurological dysfunction. Neurosurgery
48, 1393–1399; discussion 1399–1401 (2001).
95. Tesco, G. et al. Depletion of GGA3 stabilizes BACE and
enhances β‑secretase activity. Neuron 54, 721–737
96. Blasko, I. et al. Experimental traumatic brain injury in
rats stimulates the expression, production and activity
of Alzheimer’s disease β‑secretase (BACE‑1). J. Neural
Transm. 111, 523–536 (2004).
97. Shirotani, K. et al. Neprilysin degrades both amyloid β
peptides 1–40 and 1–42 most rapidly and efficiently
among thiorphan‑ and phosphoramidon‑sensitive
endopeptidases. J. Biol. Chem. 276, 21895–21901
98. Iwata, N. et al. Identification of the major Aβ1–
42‑degrading catabolic pathway in brain parenchyma:
suppression leads to biochemical and pathological
deposition. Nature Med. 6, 143–150 (2000).
99. Miners, J. S. et al. Aβ‑degrading enzymes in Alzheimer’s
disease. Brain Pathol. 18, 240–252 (2008).
100. Li, C. et al. Comparison of the structure and
expression of the human and rat neprilysin
(endopeptidase 24.11)‑encoding genes.
Gene 164, 363–366 (1995).
101. Li, C. & Hersh, L. B. Characterization of the promoter
region of the rat neprilysin gene. Arch. Biochem.
Biophys. 358, 189–195 (1998).
102. Roques, B. P., Noble, F., Dauge, V.,
Fournie‑Zaluski, M. C. & Beaumont, A. Neutral
endopeptidase 24.11: structure, inhibition, and
experimental and clinical pharmacology. Pharmacol.
Rev. 45, 87–146 (1993).
103. Turner, A. J., Isaac, R. E. & Coates, D. The neprilysin
(NEP) family of zinc metalloendopeptidases:
genomics and function. Bioessays 23, 261–269
104. Kanemitsu, H., Tomiyama, T. & Mori, H. Human
neprilysin is capable of degrading amyloid beta
peptide not only in the monomeric form but also the
pathological oligomeric form. Neurosci. Lett. 350,
105. Iwata, N. et al. Metabolic regulation of brain Aβ
by neprilysin. Science 292, 1550–1552 (2001).
106. Iwata, N., Higuchi, M. & Saido, T. C. Metabolism
of amyloid‑β peptide and Alzheimer’s disease.
Pharmacol. Ther. 108, 129–148 (2005).
107. Yasojima, K., Akiyama, H., McGeer, E. G. &
McGeer, P. L. Reduced neprilysin in high plaque areas
of Alzheimer brain: a possible relationship to deficient
degradation of β‑amyloid peptide. Neurosci. Lett. 297,
108. Koenigsknecht‑Talboo, J. et al. Rapid microglial
response around amyloid pathology after systemic
anti‑Aβ antibody administration in PDAPP mice.
J. Neurosci. 28, 14156–14164 (2008).
109. Hickman, S. E., Allison, E. K. & El Khoury, J.
Microglial dysfunction and defective β‑amyloid
clearance pathways in aging Alzheimer’s disease
mice. J. Neurosci. 28, 8354–8360 (2008).
110. Pardossi‑Piquard, R. et al. Presenilin‑dependent
transcriptional control of the Aβ‑degrading enzyme
neprilysin by intracellular domains of βAPP and APLP.
Neuron 46, 541–554 (2005).
111. Mohajeri, M. H., Wollmer, M. A. & Nitsch, R. M.
Aβ 42‑induced increase in neprilysin is associated
with prevention of amyloid plaque formation in vivo.
J. Biol. Chem. 277, 35460–35465 (2002).
112. Johnson, V. et al. A neprilysin polymorphism and
amyloid β plaques following traumatic brain injury in
humans. J. Neurotrauma 27 Mar 2009 (doi:10.1089/
113. Mattson, M. P. et al. Evidence for excitoprotective
and intraneuronal calcium‑regulating roles for
secreted forms of the β‑amyloid precursor protein.
Neuron 10, 243–254 (1993).
114. Milward, E. A. et al. The amyloid protein precursor
of Alzheimer’s disease is a mediator of the effects of
nerve growth factor on neurite outgrowth. Neuron 9,
115. Roch, J. M., Jin, L. W., Ninomiya, H., Schubert, D. &
Saitoh, T. Biologically active domain of the secreted
form of the amyloid β/A4 protein precursor. Ann. NY
Acad. Sci. 695, 149–157 (1993).
116. Small, D. H. et al. Neurite‑outgrowth regulating
functions of the amyloid protein precursor of
Alzheimer’s disease. J. Alzheimers Dis. 1, 275–285
117. Small, D. H. et al. A heparin‑binding domain in the
amyloid protein precursor of Alzheimer’s disease is
involved in the regulation of neurite outgrowth.
J. Neurosci. 14, 2117–2127 (1994).
118. Morimoto, T., Ohsawa, I., Takamura, C., Ishiguro, M. &
Kohsaka, S. Involvement of amyloid precursor protein
in functional synapse formation in cultured
hippocampal neurons. J. Neurosci. Res. 51, 185–195
119. Van den Heuvel, C. et al. Upregulation of amyloid
precursor protein messenger RNA in response to
traumatic brain injury: an ovine head impact model.
Exp. Neurol. 159, 441–450 (1999).
120. Thornton, E., Vink, R., Blumbergs, P. C. &
Van Den Heuvel, C. Soluble amyloid precursor
protein alpha reduces neuronal injury and improves
functional outcome following diffuse traumatic
brain injury in rats. Brain Res. 1094, 38–46
121. Terry, R. D. et al. Physical basis of cognitive alterations
in Alzheimer’s disease: synapse loss is the major
correlate of cognitive impairment. Ann. Neurol. 30,
122. Pathological correlates of late‑onset dementia in
a multicentre, community‑based population in
England and Wales. Neuropathology Group of the
Medical Research Council Cognitive Function and
Ageing Study (MRC CFAS). Lancet 357, 169–175
123. Engler, H. et al. Two‑year follow‑up of amyloid
deposition in patients with Alzheimer’s disease.
Brain 129, 2856–2866 (2006).
124. Holmes, C. et al. Long‑term effects of Aβ42
immunisation in Alzheimer’s disease: follow‑up of a
randomised, placebo‑controlled phase I trial. Lancet
372, 216–223 (2008).
125. Lambert, M. P. et al. Diffusible, nonfibrillar ligands
derived from Aβ1–42 are potent central nervous
system neurotoxins. Proc. Natl Acad. Sci. USA 95,
126. Hartley, D. M. et al. Protofibrillar intermediates
of amyloid β‑protein induce acute
electrophysiological changes and progressive
neurotoxicity in cortical neurons. J. Neurosci. 19,
127. Walsh, D. M., Klyubin, I., Fadeeva, J. V., Rowan, M. J.
& Selkoe, D. J. Amyloid‑β oligomers: their production,
toxicity and therapeutic inhibition. Biochem. Soc.
Trans. 30, 552–557 (2002).
128. Cleary, J. P. et al. Natural oligomers of the amyloid‑β
protein specifically disrupt cognitive function. Nature
Neurosci. 8, 79–84 (2005).
129. Lee, E. B. et al. Targeting amyloid‑β peptide (Aβ)
oligomers by passive immunization with a
conformation‑selective monoclonal antibody
improves learning and memory in Aβ precursor
protein (APP) transgenic mice. J. Biol. Chem.
281, 4292–4299 (2006).
130. Lesne, S. et al. A specific amyloid‑β protein assembly
in the brain impairs memory. Nature 440, 352–357
131. Pearson, H. A. & Peers, C. Physiological roles for
amyloid β peptides. J. Physiol. 575, 5–10 (2006).
132. Wang, Q., Walsh, D. M., Rowan, M. J., Selkoe, D. J. &
Anwyl, R. Block of long‑term potentiation by naturally
secreted and synthetic amyloid β‑peptide in
hippocampal slices is mediated via activation of the
kinases c‑Jun N‑terminal kinase, cyclin‑dependent
kinase 5, and p38 mitogen‑activated protein kinase
as well as metabotropic glutamate receptor type 5.
J. Neurosci. 24, 3370–3378 (2004).
133. Walsh, D. M. et al. Naturally secreted oligomers of
amyloid β protein potently inhibit hippocampal long‑
term potentiation in vivo. Nature 416, 535–539 (2002).
134. Shankar, G. M. et al. Amyloid‑β protein dimers isolated
directly from Alzheimer’s brains impair synaptic plasticity
and memory. Nature Med. 14, 837–842 (2008).
135. Langlois, J. A., Rutland‑Brown, W. & Wald, M. M.
The epidemiology and impact of traumatic brain
injury: a brief overview. J. Head Trauma Rehabil.
21, 375–378 (2006).
136. Bateman, R. J. et al. A γ‑secretase inhibitor decreases
amyloid‑β production in the central nervous system.
Ann. Neurol. 66, 48–54 (2009).
137. Corder, E. H. et al. Gene dose of apolipoprotein
E type 4 allele and the risk of Alzheimer’s disease
in late onset families. Science 261, 921–923 (1993).
138. Saunders, A. M. et al. Association of apolipoprotein E
allele epsilon 4 with late‑onset familial and sporadic
Alzheimer’s disease. Neurology 43, 1467–1472 (1993).
139. Teasdale, G. M., Nicoll, J. A., Murray, G. & Fiddes, M.
Association of apolipoprotein E polymorphism with
outcome after head injury. Lancet 350, 1069–1071
140. Sorbi, S. et al. ApoE as a prognostic factor for
post‑traumatic coma. Nature Med. 1, 852 (1995).
141. Friedman, G. et al. Apolipoprotein E‑ε4 genotype
predicts a poor outcome in survivors of traumatic
brain injury. Neurology 52, 244–248 (1999).
142. Liberman, J. N., Stewart, W. F., Wesnes, K. &
Troncoso, J. Apolipoprotein E ε4 and short‑term
recovery from predominantly mild brain injury.
Neurology 58, 1038–1044 (2002).
143. Sundstrom, A. et al. APOE influences on
neuropsychological function after mild head
injury: within‑person comparisons. Neurology
62, 1963–1966 (2004).
144. Lichtman, S. W., Seliger, G., Tycko, B. & Marder, K.
Apolipoprotein E and functional recovery from brain
injury following postacute rehabilitation. Neurology
55, 1536–1539 (2000).
145. Liaquat, I., Dunn, L. T., Nicoll, J. A., Teasdale, G. M. &
Norrie, J. D. Effect of apolipoprotein E genotype on
hematoma volume after trauma. J. Neurosurg. 96,
146. Smith, C., Graham, D. I., Murray, L. S., Stewart, J. &
Nicoll, J. A. Association of APOE ε4 and cerebrovascular
pathology in traumatic brain injury. J. Neurol.
Neurosurg. Psychiatry 77, 363–366 (2006).
147. Diaz‑Arrastia, R. et al. Increased risk of late
posttraumatic seizures associated with inheritance
of APOE ε4 allele. Arch. Neurol. 60, 818–822 (2003).
148. Chamelian, L., Reis, M. & Feinstein, A. Six‑month
recovery from mild to moderate traumatic brain injury:
the role of APOE‑ε4 allele. Brain 127, 2621–2628
149. Nathoo, N., Chetry, R., van Dellen, J. R., Connolly, C.
& Naidoo, R. Apolipoprotein E polymorphism and
outcome after closed traumatic brain injury: influence
of ethnic and regional differences. J. Neurosurg. 98,
NATurE rEvIEWS | NeuroscieNce
voLumE 11 | mAy 2010 | 369
© 20 Macmillan Publishers Limited. All rights reserved10
150. Teasdale, G. M., Murray, G. D. & Nicoll, J. A. The
association between APOE ε4, age and outcome
after head injury: a prospective cohort study. Brain
128, 2556–2561 (2005).
151. Mayeux, R. et al. Synergistic effects of traumatic
head injury and apolipoprotein‑ε4 in patients with
Alzheimer’s disease. Neurology 45, 555–557
152. Mayeux, R. et al. Genetic susceptibility and head
injury as risk factors for Alzheimer’s disease among
community‑dwelling elderly persons and their first‑
degree relatives. Ann. Neurol. 33, 494–501
153. Mauri, M. et al. Interaction between Apolipoprotein
ε4 and traumatic brain injury in patients with
Alzheimer’s disease and mild cognitive impairment.
Funct. Neurol. 21, 223–228 (2006).
154. Nicoll, J. A., Roberts, G. W. & Graham, D. I.
Apolipoprotein E ε4 allele is associated with
deposition of amyloid β‑protein following head injury.
Nature Med. 1, 135–137 (1995).
155. Hartman, R. E. et al. Apolipoprotein E4 influences
amyloid deposition but not cell loss after
traumatic brain injury in a mouse model of
Alzheimer’s disease. J. Neurosci. 22, 10083–10087
156. Martland, H. Punch drunk. J. Am. Med. Assoc. 91,
157. Millspaugh, J. Dementia pugilistica. US Naval Med.
Bull. 35, 297–303 (1937).
158. Roberts, G. W., Allsop, D. & Bruton, C. The occult
aftermath of boxing. J. Neurol. Neurosurg. Psychiatry
53, 373–378 (1990).
159. Roberts, A. Brain Damage in Boxers (Pitman
Publishing, London, 1969).
160. Jordan, B. D. et al. CT of 338 active professional
boxers. Radiology 185, 509–512 (1992).
161. Jordan, B. D. et al. Apolipoprotein E ε4 associated
with chronic traumatic brain injury in boxing.
JAMA 278, 136–140 (1997).
162. Guskiewicz, K. M. et al. Association between recurrent
concussion and late‑life cognitive impairment in
retired professional football players. Neurosurgery
57, 719–726 (2005).
163. Omalu, B. I. et al. Chronic traumatic encephalopathy
in a National Football League player. Neurosurgery
57, 128–134 (2005).
164. Omalu, B. I. et al. Chronic traumatic encephalopathy
in a national football league player: part II. Neurosurgery
59, 1086–1092; discussion 1092–1093 (2006).
165. McKee, A. C. et al. Chronic traumatic encephalopathy
in athletes: progressive tauopathy after repetitive head
injury. J. Neuropathol. Exp. Neurol. 68, 709–735
166. Tokuda, T., Ikeda, S., Yanagisawa, N., Ihara, Y. &
Glenner, G. G. Re‑examination of ex‑boxers’ brains
using immunohistochemistry with antibodies to
amyloid β‑protein and tau protein. Acta Neuropathol.
82, 280–285 (1991).
167. Uryu, K. et al. Repetitive mild brain trauma
accelerates Aβ deposition, lipid peroxidation, and
cognitive impairment in a transgenic mouse model
of Alzheimer amyloidosis. J. Neurosci. 22, 446–454
168. Conte, V. et al. Vitamin E reduces amyloidosis and
improves cognitive function in Tg2576 mice following
repetitive concussive brain injury. J. Neurochem.
90, 758–764 (2004).
169. Selkoe, D. J. Alzheimer’s disease: genes, proteins, and
therapy. Physiol. Rev. 81, 741–766 (2001).
170. Braak, H. & Braak, E. Neuropathological stageing
of Alzheimer‑related changes. Acta Neuropathol.
82, 239–259 (1991).
171. Forman, M. S., Trojanowski, J. Q. & Lee, V. M.
Neurodegenerative diseases: a decade of discoveries
paves the way for therapeutic breakthroughs. Nature
Med. 10, 1055–1063 (2004).
172. Corsellis, J. A., Bruton, C. J. & Freeman‑Browne, D.
The aftermath of boxing. Psychol. Med. 3, 270–303
173. Dale, G. E., Leigh, P. N., Luthert, P., Anderton, B. H. &
Roberts, G. W. Neurofibrillary tangles in dementia
pugilistica are ubiquitinated. J. Neurol. Neurosurg.
Psychiatry 54, 116–118 (1991).
174. Schmidt, M. L., Zhukareva, V., Newell, K. L., Lee, V. M. &
Trojanowski, J. Q. Tau isoform profile and phosphorylation
state in dementia pugilistica recapitulate Alzheimer’s
disease. Acta Neuropathol. 101, 518–524 (2001).
175. Smith, C., Graham, D. I., Murray, L. S. & Nicoll, J. A.
Tau immunohistochemistry in acute brain injury.
Neuropathol. Appl. Neurobiol. 29, 496–502 (2003).
176. Hoshino, S. et al. Emergence of immunoreactivities for
phosphorylated tau and amyloid‑β protein in chronic
stage of fluid percussion injury in rat brain.
Neuroreport 9, 1879–1883 (1998).
This work was supported by US National Institutes of Health
grants NS038104 and NS056202.
Competing interests statement.
The authors declare no competing financial interests
APP | BACE1 | caspase-3 | neprilysin | PS-1
Penn center for Brain injury and repair:
smith Laboratory Homepage:
All liNks Are Active iN the oNliNe PDf
Nature Reviews Neuroscience publishes items of correspondence online. Such contributions are published at the
discretion of the Editors and can be subject to peer review. Correspondence should be no longer than 500 words with
up to 15 references and should represent a scholarly attempt to comment on a specific Review or Perspective article
that has been published in the journal. To view correspondence, please go to our homepage at: http://www.nature.
com/nrn and follow the link from the current table of contents. To cite correspondence, please use its doi number.
The following correspondence has recently been published:
Beyond IQ comparisons: intra‑individual training differences
This correspondence relates to the article:
The neuroscience of human intelligence differences
Ian J. Deary, Lars Penke and Wendy Johnson
Nature Rev. Neurosci. 11, 201–211 (2010)
370 | mAy 2010 | voLumE 11
© 20 Macmillan Publishers Limited. All rights reserved 10