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to this population. Previously we found that fractionation increases OPC loss acutely. Pdgfrα-
T2
CreER :ROSA26R-YFP mice were administered tamoxifen to induce YFP expression in PDGFRα+ OPCs prior
to receiving 0 Gy, 20 Gy, or 6 Gy*6 IR, and the increased OPC death and proliferation found after exposure
to fractionated IR suggests that accelerated repopulation contributes to the increased OPC loss seen 3
days after the last exposure. The impact of this acute loss of OPCs over time, however, is still unclear. We
hypothesize that damage to OPCs and the microenvironment from IR exposure will impair OPC recovery.
In order to determine the impact of fractionated versus single dose IR exposure on recovery of OPCs,
T2
Pdgfrα-CreER :ROSA26R-YFP mice again received tamoxifen prior to single or fractionated IR and
recovery was assessed at 1, 2, 3, and 4 weeks after exposure. In addition, OPCs were isolated from single
and fractionated IR animals and colony forming assays were performed to determine if cell intrinsic
damage resulted from exposure. This data that assesses the ability of OPCs to recover after irradiation
exposure will help us understand the potential long term implications of acute IR-induced OPC loss.
This research was supported by the Center for Medical Countermeasures against Radiation Program, U19-
AI091036, National Institute of Allergy and Infectious Diseases and the National Institute of Environmental
Health Sciences, T32-ES07026.
(PS4-78) Persistent neurocognitive decline, vascular and epithelial damage in the choroid plexus, and
1
1
β-amyloid plaques after cranial HZE radiation exposure. Andrew J. Wyrobek, PhD ; Sandhya Bhatnagar ;
1
2
and Bernard Rabin, PhD, Lawrence Berkeley National Laboratory, Berkeley, CA and University of
2
Maryland, Baltimore Campus, Baltimore, MD
Neurotoxic exposures of the CNS early in life may accelerate neurocognitive declines and hasten
the onset of neurological diseases such as Alzheimer. Understanding the molecular mechanisms of
persistent CNS risks after exposures to ionizing radiation is of special importance for patients receiving
cranial radiotherapy and for astronauts returning from extended space missions. We employed an
outbred rat model (Sprague Dawley) to investigate the time-course of CNS damage after HZE irradiation
with 56Fe (1 Gev/n; 10 or 100 cGy), using age-matched shams and young animals as reference. Irradiated
rats showed persistent neurocognitive deficits on novel object recognition and bar press assays. CNS
transcriptomic findings pointed to radiation damage in the choroid plexus (CP), the structure that
produces cerebral spinal fluid (CSF), and β-amyloid plaques. Groups of rats were exposed at 2 or 6 months
(m) of age and CNS tissue was sampled at 4, 9 or 21 m later. Beginning at 4 m after exposure, there was
increased CP endothelial fibrinogen-positive fibrosis especially in small fenestrated capillary vessels, and
the CP epithelium produced less transthyrethin (Ttr) protein, a major component of CSF. Ttr is a β-amyloid
binding protein that facilitates its clearance. We observed a progressive increase in β-amyloid plaques
beginning at 9 m after exposure, using Congo red staining and β-amyloid immunohistochemistry. Un-
irradiated animals did not show age-related changes in CP fibrosis or Ttr expression, but showed a small
increase in plaque frequency with age. Our findings are consistent with the hypothesis that HZE exposures
early in life can accelerate the onset of CP endothelial and epithelial dysfunctions that may diminish the
production of molecular factors required for β-amyloid clearance and prevention of β-amyloid plaque
build-up in advanced aging. [Supported by NASA NNX14AC86G (AJW) and NNJ06HD93G (BR) at LBNL
under DE-AC02-05CH11231.]
278 | P a g e
T2
CreER :ROSA26R-YFP mice were administered tamoxifen to induce YFP expression in PDGFRα+ OPCs prior
to receiving 0 Gy, 20 Gy, or 6 Gy*6 IR, and the increased OPC death and proliferation found after exposure
to fractionated IR suggests that accelerated repopulation contributes to the increased OPC loss seen 3
days after the last exposure. The impact of this acute loss of OPCs over time, however, is still unclear. We
hypothesize that damage to OPCs and the microenvironment from IR exposure will impair OPC recovery.
In order to determine the impact of fractionated versus single dose IR exposure on recovery of OPCs,
T2
Pdgfrα-CreER :ROSA26R-YFP mice again received tamoxifen prior to single or fractionated IR and
recovery was assessed at 1, 2, 3, and 4 weeks after exposure. In addition, OPCs were isolated from single
and fractionated IR animals and colony forming assays were performed to determine if cell intrinsic
damage resulted from exposure. This data that assesses the ability of OPCs to recover after irradiation
exposure will help us understand the potential long term implications of acute IR-induced OPC loss.
This research was supported by the Center for Medical Countermeasures against Radiation Program, U19-
AI091036, National Institute of Allergy and Infectious Diseases and the National Institute of Environmental
Health Sciences, T32-ES07026.
(PS4-78) Persistent neurocognitive decline, vascular and epithelial damage in the choroid plexus, and
1
1
β-amyloid plaques after cranial HZE radiation exposure. Andrew J. Wyrobek, PhD ; Sandhya Bhatnagar ;
1
2
and Bernard Rabin, PhD, Lawrence Berkeley National Laboratory, Berkeley, CA and University of
2
Maryland, Baltimore Campus, Baltimore, MD
Neurotoxic exposures of the CNS early in life may accelerate neurocognitive declines and hasten
the onset of neurological diseases such as Alzheimer. Understanding the molecular mechanisms of
persistent CNS risks after exposures to ionizing radiation is of special importance for patients receiving
cranial radiotherapy and for astronauts returning from extended space missions. We employed an
outbred rat model (Sprague Dawley) to investigate the time-course of CNS damage after HZE irradiation
with 56Fe (1 Gev/n; 10 or 100 cGy), using age-matched shams and young animals as reference. Irradiated
rats showed persistent neurocognitive deficits on novel object recognition and bar press assays. CNS
transcriptomic findings pointed to radiation damage in the choroid plexus (CP), the structure that
produces cerebral spinal fluid (CSF), and β-amyloid plaques. Groups of rats were exposed at 2 or 6 months
(m) of age and CNS tissue was sampled at 4, 9 or 21 m later. Beginning at 4 m after exposure, there was
increased CP endothelial fibrinogen-positive fibrosis especially in small fenestrated capillary vessels, and
the CP epithelium produced less transthyrethin (Ttr) protein, a major component of CSF. Ttr is a β-amyloid
binding protein that facilitates its clearance. We observed a progressive increase in β-amyloid plaques
beginning at 9 m after exposure, using Congo red staining and β-amyloid immunohistochemistry. Un-
irradiated animals did not show age-related changes in CP fibrosis or Ttr expression, but showed a small
increase in plaque frequency with age. Our findings are consistent with the hypothesis that HZE exposures
early in life can accelerate the onset of CP endothelial and epithelial dysfunctions that may diminish the
production of molecular factors required for β-amyloid clearance and prevention of β-amyloid plaque
build-up in advanced aging. [Supported by NASA NNX14AC86G (AJW) and NNJ06HD93G (BR) at LBNL
under DE-AC02-05CH11231.]
278 | P a g e
