Page 104 - NNS 2014 Program & Abstract Book

B5-05
BLAST EXPOSURE PHOSPHORYLATES TAU PRE-
FERENTIALLY AT SERINE396, WHICH CAN TRIGGER
ALZHEIMER’S-LIKE PATHOLOGY
Arun, P., Wilder, D., Edwards, E., Wang, Y., Gist, I., Long, J.B.
Walter Reed Army Institute of Research, Blast-Induced Neurotrauma
Branch, Center for Military Psychiatry & Neurosciences, Silver
Spring, Maryland, USA
Blast-induced traumatic brain injury (TBI) is one of the major dis-
abilities in service members returning from recent military opera-
tions. Blast-induced TBI is associated with acute and chronic
neuropathological and neurobehavioral deficits. Epidemiological
studies indicate that brains of 30% of victims who die acutely fol-
lowing TBI have A b plaques, a pathological feature of Alzheimer’s
disease (AD), which suggests that TBI may predispose to AD, al-
though to date this notion remains somewhat speculative. Tau pro-
tein, phosphorylated at serine396 (S396), is rich in paired helical
filaments which form neurofibrillary tangles (NFTs) observed in the
brains of patients with AD. The number of NFTs is tightly linked to
the degree of dementia, indicating that the formation of NFTs may
underlie and contribute to neuronal dysfunction. Preliminary studies
carried out in our laboratory using shock tube models of single and
repeated blast-induced TBI in rats indicate that phosphorylation of
Tau protein occurs preferentially at S396. S396 phosphorylation of
Tau varied in different regions of the brain and the degree of
phosphorylation increased with number of blast exposures. Increased
S396 phosphorylation occurred acutely after blast exposures and
chronically returned towards normal levels which at this stage did
not positively correlate with the accumulation of amyloid precursor
protein (APP) that occurred chronically. These results indicate that
acute Tau protein phosphorylation at S396 and chronic accumulation
of APP in the brain after blast exposure may predispose to Alzhei-
mer’s-like disease.
Key words
Alzheimer’s disease, Alzheimer’s-like pathology, blast exposure,
traumatic brain injury
B5-06
PROLONGED INCREASES IN 22 KDA TAU FRAGMENT
FOLLOWING PENETRATING TBI
Cartagena, C.M. , Rammelkamp, Z., Phillips, K.L., Tortella, F.C.,
Schmid, K.E.
Walter Reed Army Institute of Research, Silver Spring, MD, USA
Tau is a protein involved in stabilizing microtubules in axons. Here
we determine whether there are changes in levels of tau or tau frag-
ments within the acute and subacute time frames following pene-
trating ballistic-like brain injury (PBBI). PBBI involves the rapid
inflation/deflation of a custom probe causing a temporary cavity that
in this case equaled 10% of total brain volume. Brain tissue was
collected ipsilaterally within the injury tract at 4 and 24 hr, 3 and 7
days post-injury (n = 8 - 10). Tau levels and tau fragmentation was
analyzed by immunoblot and normalized to beta-actin levels. Tau
levels during PBBI are compared to probe only (no temporary cavity)
and sham controls. Full length tau levels (55 kDa) were not altered 4
hr post-injury. By 24 hr post-injury, probe and PBBI tau levels were
decreased 39% and 42%, respectively. At 3 days post-injury 73% and
89%, respectively; and at 7 days post-injury 87% and 96%, respec-
tively. A 40 kDa fragment showed similar temporal decreases: 35%
(probe, p < 0.05) and 45% (PBBI, p < 0.05) at 24 hr, 78% (probe,
p < 0.001) and 94% (PBBI, p < 0.001) at 3 days, and 80% (probe,
p < 0.001) and 93% (PBBI, p < 0.001) at 7 days. In contrast, a 22 kDa
tau fragment, known for its involvement in tauopathies, including
Alzheimer’s disease, increased dramatically following injury: 544%
(probe, p < 0.01) and 1541% (PBBI, p < 0.001) at 4 hr and 893%
(probe, p < 0.05) and 2367% (PBBI, p < 0.01) at 24 hr. At 3 and 7
days post-injury PBBI levels again were significantly increased
1541% and 2424%, respectively Changes in tau levels and tau
fragment levels are clearly influenced by injury severity (probe vs
PBBI). Ongoing studies will determine if the dramatic increases in
the 22 kDa tau fragment can be detected at more chronic time-points
(i.e. month post-PBBI). Collectively, these early changes in tau
fragmentation may be useful as prognostic indicators of neurode-
generative tauopathies utilizing in vivo neuroimaging such at posi-
tron emission tomography, and as early markers of therapeutic
efficacy.
Key words
neurodegeneration, PBBI, severe TBI, tau
C1-01
MATRIX METALLOPROTEINASES AS A THERAPEUTIC
TARGET FOR SUPPORTING UROLOGIC RECOVERY IN A
MURINE MODEL OF SPINAL CORD INJURY
Fandel, T.M.1 , Trivedi, A.1, Martinez, A.F.1, Zhang, H.1, Levine,
J.M.2, Noble-Haeusslein, L.J.1
1University of California, Department of Neurosurgery, San Fran-
cisco, USA
2Texas A&M University, Department of Small Animal Clinical Sci-
ences, College Station, USA
Matrix-metalloproteinases (MMPs), and in particular MMP-9, are
upregulated in the acutely injured spinal cord and their transient,
short-term blockade with a general MMP-inhibitor (MMPI), begin-
ning 3 hours post-injury and for the next 3 days, results in long-term
locomotor recovery and greater sparing of white matter. As sparing
of white matter may at least in part reflect preservation of long
descending fiber tracts including those involved in the control of
bladder function, we hypothesized that acute blockade of MMPs
would lead to improved urological function. Testing this hypothesis,
we conducted a randomized, blinded pre-clinical study, in which
adult male C57Bl/6 mice were subjected to a moderate contusion
injury (n = 23) at the level T9 and were treated with either an MMPI
or vehicle. As neutrophils are a major source of MMP-9, treatments
were initiated 8 hours after injury, a time corresponding to promi-
nent neutrophilia in the humoral compartment. Neurological and
urological recovery was assessed using the Basso Mouse Scale and
conscious cystometry, over a period of 5 weeks and at 6 weeks post-
injury, respectively. Stereology was used to determine lesion volume
and white matter sparing. As bladder dysfunction is associated with
aberrant wound healing resulting in increased bladder wall thick-
ness, this parameter was measured at the time of euthanasia. In the
MMPI-treated group there were significant long-term improvements
in locomotor function, sparing of white matter and voiding function,
as evidenced by decreased post-void residual urine and enhanced
voiding efficacy. Moreover, there were fewer uninhibited bladder
contractions per voiding cycle, an indicator of decreased bladder
over-activity, and detrusor wall thickness was significantly less
compared to vehicle controls. In summary, delayed treatment with
an MMPI improved both locomotor and bladder function. These
A-72