Page 144 - NNS 2014 Program & Abstract Book

D1-32
GENETIC DELETION OF PARKIN ENHANCES RECOVERY
FROM TBI
Saldana-Prieto, E., Balarezo, M., Cox, R., Villapol, S., Symes, A.J.
Uniformed Service University, Department of Pharmacology and
Center for Neuroscience and Regenerative Medicine, Bethesda, MD,
USA
Parkin is an E3 ubiquitin ligase that functions to target substrates for
proteosomal degradation. Loss of function mutations to the gene en-
coding Parkin are linked to the development of autosomal recessive
Parkinson’s disease. Parkin is neuroprotective, protecting neurons in a
variety of different stress paradigms. Little is known about Parkin
function after traumatic brain injury (TBI). As TBI results in signif-
icant secondary damage, including oxidative stress, we hypothesized
that Parkin would act as a neuroprotective factor after TBI. We
therefore examined Parkin expression in mice after controlled cortical
impact (CCI), and compared the recovery of Parkin knockout mice to
control mice after CCI. We performed CCI over the somatosensory
cortex of 9 week old male and female wild-type and Parkin null mice.
All mice were sacrificed at 3 dpi. In wild type mice we found sig-
nificantly elevated Parkin expression in the soma and axons of neu-
rons in the peri-lesional area, but not in the lesion centre after CCI.
Some microglial cells in the cortex and hippocampus also expressed
Parkin after injury. Surprisingly, we found that Parkin null mice had
fewer TUNEL positive cells in injured cortex at 3 dpi than wild type
mice, suggesting that the absence of Parkin protected against acute
cell death after CCI. The cortical lesion volume did not differ between
the two groups. Parkin null male mice had significantly less GFAP
immunoreactivity than wild type mice in the peri-lesional area after
CCI. There was no difference in GFAP immunoreactivity in female
mice. We also found increased nuclear immunoreactivity for TDP-43
in Parkin null male mice. Taken together our results suggest that the
absence of Parkin enhanced some features of the recovery from brain
injury. As Parkin has been linked to autophagy and mitophagy in
particular, these Parkin null mice may help in the investigation of the
role of these pathways in neuronal survival after TBI.
Key words
autophagy, mice, parkin, TDP-43
D1-33
CHRONIC ADMINISTRATION OF RESVERATROL AFTER
MILD TBI REDUCES BETA-AMYLOID PLAQUE LOAD IN
THE BRAIN OF 5XFAD MICE
Gatson, J.W.1, Liu, M.M.1 , Minei, J.P.1 , Madden, C.1 , Batjer, H.1,
Diaz-Arrastia, R.2
1University of Texas Southwestern Medical Center, Dallas, TX, USA
2Uniformed Services University of the Health Sciences, Rockville,
MD, USA
Traumatic brain injury (TBI) is a major risk factor for the develop-
ment of Alzheimer’s disease (AD) and the link between TBI and
Alzheimer’s-like dementia has been studied extensively in both ani-
mals and humans.
In this closed-head mild TBI model, the impactor tip was aligned
on the skull on the sagittal suture midway between the bregma and
lambda sutures. The 2-month old male 5XFAD mice were injured at a
depth of 1.5 mm, velocity of 3.5 m/sec, and a delay time of 100 msec
using the controlled cortical impact (CCI) device. After injury, mice
were treated with a subcutaneous dose of either placebo (corn oil) or
resveratrol (100 mg/kg) at 5 minutes, 12 hours (hrs), 24 hrs, 48 hrs,
and 72 hrs after mild TBI. At 30 days after injury, the animals were
intra-cardially perfused with 0.9% saline followed by 10% phosphate-
buffered formalin. Whole brain sections were stained for beta-amyloid
and GFAP (astrocytes).
In this study we found that in the placebo+ TBI treatment group there
was a significant increase in the number of amyloid plaques within the
cerebral cortex on day 30 (p < 0.03) and 60 (p < 0.05) after injury
compared to the control animals. Resveratrol treatment resulted in re-
duced plaque load on day 30 (p < 0.05) and 60 (p < 0.05). In the cortex
an increase in the number of astrocytes was also observed on day 30
(p < 0.04) and 60 (p < 0.05) after injury, but a resveratrol-mediated de-
crease in the number of astrocytes occurred only on day 60 after injury.
Resveratrol treatment lowers beta-amyloid plaque load and chronic
neuro-inflammation in 5XFAD mice. These results suggest that re-
sveratrol may be beneficial in reducing chronic secondary brain injury
and Alzheimer’s-like pathology after suffering a mild TBI.
Key word
beta-amyloid
D1-34
MICRORNAS REGULATE MITOPHAGY AFTER TRAU-
MATIC BRAIN INJURY
Chao, H.1, Xu, X.1, Liu, N.1, You, Y.1, Ji, J.1,2, Bayir, H.2
1Nanjing Medical University, Nanjing, China
2University of Pittsburgh, Pittsburgh, USA
MicroRNAs (MiRs) are RNA molecules composed of 20–24 nucleotides
that function to inhibit mRNA translation, and have key roles in normal
CNS development and function, as well as in disease condition. Pre-
viously, we found that mitophagy can happen one hour after stretch in
the primary cortical neurons and in vivo animal CCI models. In the
current report, in addition, we found that mitophagy can happen in the
peri-contusional human brain tissue. And furthermore, we found that one
hour after mechanical stretch in primary cortical neurons and in human
trauma tissue, miR-let-7i, miR-16, miR-92a, and miR-765 all signifi-
cantly increased compared with sham controls; however, MiR-137, MiR-
21, and MiR-10 significantly decreased. Interestingly, overexpression of
MiR-137, MiR-21, and MiR-10 can suppress the mechanical stretch
induced mitophagy in primary neurons, but not affect bulk autophagy.
When the neurons were transfected with cadiolipin synthase (CLS),
mechanical stretch only caused significant decrease of MiR-137 but not
MiR-21 and MiR-10. The current data suggested that MiR-137 might
regulate neuronal mitophagy through CLS-LC3 pathway. Considering
the current neuroprotection strategy about mitophagy, this regulation
may introduce a novel therapeutic target. Further detailed mechanism
about the miRNA and mitophagy after TBI will be investigated.
Key words
microRNA, mitophagy, neuroprotection
D1-35
CX3CR1 DEFICIENCY AMELIORATES TBI-INDUCED
INFLAMMATORY RESPONSE AND COGNITIVE DYS-
FUNCTION
Morganti, J.M., Jopson, T.D., Riparip, L.K., Rosi, S.
University of California, San Francisco, USA
A-112