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Project Title:  Impact of Space-Radiation Induced Alterations on Toxic Protein Accumulation Associated with Neurodegenerative Disease Reduce
Images: icon  Fiscal Year: FY 2021 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 01/29/2016  
End Date: 11/28/2020  
Task Last Updated: 02/25/2021 
Download report in PDF pdf
Principal Investigator/Affiliation:   O'Banion, Kerry  M.D., Ph.D. / University of Rochester 
Address:  Box 603  
601 Elmwood Ave 
Rochester , NY 14642-0001 
Email: kerry_obanion@urmc.rochester.edu 
Phone: 585-275-5185  
Congressional District: 25 
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Rochester 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Deane, Rashid  Ph.D. University of Rochester 
Majewska, Anna  Ph.D. University of Rochester 
Williams, Jacqueline  Ph.D. University of Rochester 
Key Personnel Changes / Previous PI: November 2016: There have been no changes to key personnel.
Project Information: Grant/Contract No. NNX16AE07G 
Responsible Center: NASA JSC 
Grant Monitor: Elgart, Robin  
Center Contact: 281-244-0596 (o)/832-221-4576 (m) 
shona.elgart@nasa.gov 
Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-RADIATION. Appendix D: Ground-Based Studies in Space Radiobiology 
Grant/Contract No.: NNX16AE07G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Bmed:Risk of Adverse Behavioral Conditions and Psychiatric Disorders
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
Flight Assignment/Project Notes: NOTE: End date changed to 11/28/2020 per NSSC information (Ed., 8/25/20)

Task Description: In addition to the risk of cancer, there is concern that prolonged exposure of astronauts to deep space radiation will lead to degenerative changes in different organ systems, including the brain. Indeed we previously demonstrated that space radiation impaired cognitive performance and exacerbated Alzheimer’s disease (AD) pathology in a widely used mouse model of AD. Accumulation of the toxic peptide amyloid-ß occurs in AD and has been clearly established as an inherited cause of the disease. Space radiation at relatively modest doses elicits chronic inflammation and oxidative stress responses that alter normal brain function and may contribute to amyloid-ß accumulation by inhibiting normal clearance mechanisms. Recent data from our laboratory shows reduced clearance of amyloid-ß in mouse brain many months after exposure to space radiation. Thus, we hypothesize that radiation exacerbates Alzheimer’s disease pathology by altering the ability of the brain to remove amyloid-ß. To address this hypothesis we propose experiments that explore three possible cellular mechanisms linking radiation-induced neuroinflammation to reduced amyloid-ß clearance. We also propose to determine whether a drug that reduces brain inflammation and enhances amyloid-ß clearance can mitigate radiation-induced changes in Alzheimer’s pathology and cognitive decline in a mouse model of the disease. Taken together, these studies will lead to a better understanding of the biological mechanisms underlying risks for neurodegenerative disease after space radiation exposure.

Research Impact/Earth Benefits: Our research explores mechanisms by which toxic proteins involved in neurodegenerative diseases might accumulate in brain tissue following radiation exposure. Our results in mice using space-relevant radiation types and doses may inform about possible risks to individuals exposed to radiation on Earth whether during medical procedures or unplanned accidental exposures.

Task Progress & Bibliography Information FY2021 
Task Progress: Summary of Major Findings

Aim 1

• Abeta clearance was reduced at 4, 8, and 12 months following 50 cGy 600 MeV/µ iron exposure

• An anti-LRP1 antibody inhibited Abeta clearance

• We were not able to reproducibly demonstrate changes in LRP1 protein expression in isolated microvessels by Western blot; we believe this is a technical issue related to variability in vessel isolation

• Abeta clearance was reduced at 4 months following exposure to silicon (50 cGy 300 MeV/µ), protons (100 cGy SPE), and a lower dose of iron (10 cGy)

Aim 2

• For nearly all the conditions tested, inulin clearance was not affected by radiation

• Glymphatic flow assessed by penetration of radiotracers from the CSF (cerebrospinal fluid) was not influenced by 50 cGy iron (600 MeV/µ), 4 months post-irradiation

• We were not able to show clear evidence of changes in astrocyte endfeet association with the vasculature after radiation

Aim 3

• Unlike our findings with low-LET (linear energy transfer) radiation (at higher doses), initial analysis of microglial proliferation in irradiated male mice after cortical needle stab injury showed variable results, but suggest that low radiation doses increased proliferation

• Our RNAseq analysis of microglia, six months after irradiation showed fewer changes with space radiation (iron, silicon or protons) than a high dose (20 Gy) of low-LET (linear energy transfer) radiation

• RNAseq analysis of microglia, 6 months after space irradiation, revealed more changes in male mice than in female mice

• Interestingly, with both types of radiation there was a greater number of downregulated transcripts

Aim 4

• Fluvastatin treatment mitigates reduced Abeta clearance using radiolabeled tracers in mice irradiated with 50 cGy iron (600 MeV/µ). This is a very exciting finding that is consistent with previously observed effects of statin treatment on LRP1 dependent Abeta transport.

• We observed a trend for reduced novel object performance in female APP/PS1 mice irradiated with 50 cGy iron (600 MeV/n), but did not see clear effects of radiation or fluvastatin in irradiated male APP/PS1 mice

• Initial analysis of amyloid deposition in this experiment showed no effect of radiation (50 cGy iron, 600 MeV/n) in female APP/PS1 mice and variable effects in male mice, which were run in three separate groups

Bibliography Type: Description: (Last Updated: 03/09/2021) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Belcher EK, Sweet TB, Karaahmet B, Dionisio-Santos DA, Owlett LA, Leffler KA, Janelsins MC, Williams JP, Olschowka JA, O'Banion MK. "Cranial irradiation acutely and persistently impairs injury-induced microglial proliferation." Brain Behav Immun – Health. 2020 Apr 4:100057. https://doi.org/10.1016/j.bbih.2020.100057 , Apr-2020
Articles in Peer-reviewed Journals Owlett L, Belcher E, Dionisio-Santos D, Williams JP, Olschowka JA, O'Banion MK. "Space radiation does not alter amyloid or tau pathology in the 3xTg mouse model of Alzheimer’s disease." Life Sci Space Res. 2020 Nov;27:89-98. https://doi.org/10.1016/j.lssr.2020.08.001 , Nov-2020
Project Title:  Impact of Space-Radiation Induced Alterations on Toxic Protein Accumulation Associated with Neurodegenerative Disease Reduce
Images: icon  Fiscal Year: FY 2020 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 01/29/2016  
End Date: 11/28/2020  
Task Last Updated: 09/17/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   O'Banion, Kerry  M.D., Ph.D. / University of Rochester 
Address:  Box 603  
601 Elmwood Ave 
Rochester , NY 14642-0001 
Email: kerry_obanion@urmc.rochester.edu 
Phone: 585-275-5185  
Congressional District: 25 
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Rochester 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Deane, Rashid  Ph.D. University of Rochester 
Majewska, Anna  Ph.D. University of Rochester 
Williams, Jacqueline  Ph.D. University of Rochester 
Key Personnel Changes / Previous PI: November 2016: There have been no changes to key personnel.
Project Information: Grant/Contract No. NNX16AE07G 
Responsible Center: NASA JSC 
Grant Monitor: Elgart, Robin  
Center Contact: 281-244-0596 (o)/832-221-4576 (m) 
shona.elgart@nasa.gov 
Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-RADIATION. Appendix D: Ground-Based Studies in Space Radiobiology 
Grant/Contract No.: NNX16AE07G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Bmed:Risk of Adverse Behavioral Conditions and Psychiatric Disorders
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
Flight Assignment/Project Notes: NOTE: End date changed to 11/28/2020 per NSSC information (Ed., 8/25/20)

Task Description: In addition to the risk of cancer, there is concern that prolonged exposure of astronauts to deep space radiation will lead to degenerative changes in different organ systems, including the brain. Indeed we previously demonstrated that space radiation impaired cognitive performance and exacerbated Alzheimer’s disease (AD) pathology in a widely used mouse model of AD. Accumulation of the toxic peptide amyloid-ß occurs in AD and has been clearly established as an inherited cause of the disease. Space radiation at relatively modest doses elicits chronic inflammation and oxidative stress responses that alter normal brain function and may contribute to amyloid-ß accumulation by inhibiting normal clearance mechanisms. Recent data from our laboratory shows reduced clearance of amyloid-ß in mouse brain many months after exposure to space radiation. Thus, we hypothesize that radiation exacerbates Alzheimer’s disease pathology by altering the ability of the brain to remove amyloid-ß. To address this hypothesis we propose experiments that explore three possible cellular mechanisms linking radiation-induced neuroinflammation to reduced amyloid-ß clearance. We also propose to determine whether a drug that reduces brain inflammation and enhances amyloid-ß clearance can mitigate radiation-induced changes in Alzheimer’s pathology and cognitive decline in a mouse model of the disease. Taken together, these studies will lead to a better understanding of the biological mechanisms underlying risks for neurodegenerative disease after space radiation exposure.

Research Impact/Earth Benefits: Our research explores mechanisms by which toxic proteins involved in neurodegenerative diseases might accumulate in brain tissue following radiation exposure. Our results in mice using space-relevant radiation types and doses may inform about possible risks to individuals exposed to radiation on Earth whether during medical procedures or unplanned accidental exposures.

Task Progress & Bibliography Information FY2020 
Task Progress: Reporting period: January 29, 2019 – January 28, 2020.

In this fourth year of the grant we carried out irradiations at NASA Space Radiation Laboratory (NSRL) for 2 of our proposed experiments and a new supplemental experiment. More specifically, during NSRL Run 19B, we irradiated 80, 6-month old C57BL/6 female mice with 50 cGy 600 MeV/µ iron, 50 cGy 300 MeV/µ silicon, or 100 cGy protons mimicking an solar particle event (SPE) as a supplement to Experiment 3.1. We also ran 47 additional male and female APP/PS1 mice with iron (50 cGy, 600 MeV/µ) for Experiment 4.1. Finally, as part of a graduate student supplement to this award, we irradiated a total of 80 Thy1-eYGP transgenic mice with or without CR3, male and female with 50 cGy SimGCRSim (n = 10 per group). In all cases appropriate numbers of sham-irradiated mice were similarly processed at the NSRL (e.g., placed in holders for similar times), but not exposed to radiation. All mice were shipped back to Rochester for further experiments.

We carried out all behavioral and tissue collections with these animals during the grant period or during a period in 2020 when our laboratory was effectively shutdown due to COVID-19 based on special permission to complete ongoing “irreplaceable” animal based studies. This shutdown slowed our progress with carrying out tissue analyses of mice from experiments 3.1 and 4.1, which are now underway and will be completed in the current and final grant period. We presented three sets of results from this work at the NASA Human Research Program Investigators’ Workshop in 2020 and have published 3 CNS (central nervous system) radiation papers (one in 2019, two in 2020) that were partially supported by this grant.

Bibliography Type: Description: (Last Updated: 03/09/2021) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings O’Banion MK, Deane R, Belcher E, Hinkle J, Dionisio-Santos D, Williams JP, Olschowka JA. "Impact of space-radiation induced alterations on toxic protein accumulation associated with neurodegenerative disease." Presented at 2020 NASA Human Research Program Investigators’ Workshop and 30th Annual Space Radiation Investigator’s Workshop, Galveston, TX, January 27-30, 2020.

Conference Program. 2020 NASA Human Research Program Investigators’ Workshop and 30th Annual Space Radiation Investigator’s Workshop, Galveston, TX, January 27-30, 2020. , Jan-2020

Abstracts for Journals and Proceedings Hinkle J, O’Banion MK, Olschowka J. "Does microglial CR3 expression modulate space radiation dependent CNS damage?" Presented at 2020 NASA Human Research Program Investigators’ Workshop and 30th Annual Space Radiation Investigator’s Workshop, Galveston, TX, January 27-30, 2020.

Conference Program. 2020 NASA Human Research Program Investigators’ Workshop and 30th Annual Space Radiation Investigator’s Workshop, Galveston, TX, January 27-30, 2020. , Jan-2020

Articles in Peer-reviewed Journals Hinkle JJ, Olschowka JA, Love TM, Williams JP, O'Banion MK. "Cranial irradiation mediated spine loss is sex-specific and complement receptor-3 dependent in male mice." Sci Rep. 2019 Dec 11;9(1):18899. https://doi.org/10.1038/s41598-019-55366-6 ; PubMed PMID: 31827187; PubMed Central PMCID: PMC6906384 , Dec-2019
Articles in Peer-reviewed Journals Dionisio-Santos DA, Olschowka JA, O'Banion MK. "Exploiting microglial and peripheral immune cell crosstalk to treat Alzheimer's disease." J Neuroinflammation. 2019 Apr 5;16(1):74. Review. https://doi.org/10.1186/s12974-019-1453-0 ; PMID: 30953557; PMCID: PMC6449993 , Apr-2019
Project Title:  Impact of Space-Radiation Induced Alterations on Toxic Protein Accumulation Associated with Neurodegenerative Disease Reduce
Images: icon  Fiscal Year: FY 2019 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 01/29/2016  
End Date: 01/28/2020  
Task Last Updated: 12/02/2018 
Download report in PDF pdf
Principal Investigator/Affiliation:   O'Banion, Kerry  M.D., Ph.D. / University of Rochester 
Address:  Box 603  
601 Elmwood Ave 
Rochester , NY 14642-0001 
Email: kerry_obanion@urmc.rochester.edu 
Phone: 585-275-5185  
Congressional District: 25 
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Rochester 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Deane, Rashid  Ph.D. University of Rochester 
Majewska, Anna  Ph.D. University of Rochester 
Williams, Jacqueline  Ph.D. University of Rochester 
Key Personnel Changes / Previous PI: November 2016: There have been no changes to key personnel.
Project Information: Grant/Contract No. NNX16AE07G 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-RADIATION. Appendix D: Ground-Based Studies in Space Radiobiology 
Grant/Contract No.: NNX16AE07G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Bmed:Risk of Adverse Behavioral Conditions and Psychiatric Disorders
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
Task Description: In addition to the risk of cancer, there is concern that prolonged exposure of astronauts to deep space radiation will lead to degenerative changes in different organ systems, including the brain. Indeed we previously demonstrated that space radiation impaired cognitive performance and exacerbated Alzheimer’s disease (AD) pathology in a widely used mouse model of AD. Accumulation of the toxic peptide amyloid-ß occurs in AD and has been clearly established as an inherited cause of the disease. Space radiation at relatively modest doses elicits chronic inflammation and oxidative stress responses that alter normal brain function and may contribute to amyloid-ß accumulation by inhibiting normal clearance mechanisms. Recent data from our laboratory shows reduced clearance of amyloid-ß in mouse brain many months after exposure to space radiation. Thus, we hypothesize that radiation exacerbates Alzheimer’s disease pathology by altering the ability of the brain to remove amyloid-ß. To address this hypothesis we propose experiments that explore three possible cellular mechanisms linking radiation-induced neuroinflammation to reduced amyloid-ß clearance. We also propose to determine whether a drug that reduces brain inflammation and enhances amyloid-ß clearance can mitigate radiation-induced changes in Alzheimer’s pathology and cognitive decline in a mouse model of the disease. Taken together, these studies will lead to a better understanding of the biological mechanisms underlying risks for neurodegenerative disease after space radiation exposure.

Research Impact/Earth Benefits: Our research explores mechanisms by which toxic proteins involved in neurodegenerative diseases might accumulate in brain tissue following radiation exposure. Our results in mice using space-relevant radiation types and doses may inform about possible risks to individuals exposed to radiation on Earth whether during medical procedures or unplanned accidental exposures.

Task Progress & Bibliography Information FY2019 
Task Progress: In this third year of the grant we carried out irradiations at NASA Space Radiation Laboratory (NSRL) for 2 of our proposed experiments and a new supplemental experiment. More specifically, during NSRL Run 18A, we irradiated 58, 4-month old APP/PS1 male and female mice with 50 cGy 600 MeV/µ iron particles for Experiment 4.2; during NSRL-18B we irradiated another 48, 4-month old APP/PS1 male and female mice with iron (50 cGy, 600 MeV/µ) for Experiment 4.1. Our team returned to Brookhaven during NSRL18C to expose 57 APP/PS1 and 68 wild-type (C57BL/6) mice to 500 mGy of the NSRL-GCRSim field, given acutely as one dose (October 8) or in 24 fractions (20.83 mGy/day; 6 days a week for 4 weeks; Oct 8-Nov 3). In all cases appropriate numbers of sham-irradiated mice were similarly processed at the NSRL (e.g., placed in holders for similar times), but not exposed to radiation. All mice were shipped back to Rochester for further experiments.

We completed our initial analysis of microglial proliferation in brain sections following needle stab injury and found no clear evidence for changes in this response, six months following particle irradiation with iron (50 cGy, 600 MeV/µ, silicon (50 cGy, 300 MeV/µ), or protons (100 cGy, SPE). Additional analyses of microglial morphology, activation, and gene expression are in process. These studies were all carried out with male mice. Similar studies are planned for female mice to be irradiated in the coming grant period (NSRL-19B) as an additional supplemental study. Studies to examine effects of radiation on microglial phagocytosis of amyloid plaques (Experiment 3.2) are planned in the next grant period with irradiation of APP/PS1 mice taking place during NSRL-19B.

We completed our first experiment (4.2) with irradiated APP/PS1 mice that had been treated with Fluvastatin. In these mice, Abeta clearance measured by infusion of 125l-labeled Abeta1-40 was reduced 6 months following 50 cGy iron (600 MeV/µ) exposure, and this effect was mitigated by 2 months of Fluvastatin treatment. These results are consistent with findings reported last year that particle radiation reduces active Abeta transport, which is primarily due to low-density lipoprotein (LDL) receptor-related protein-1 (LRP1) activity. Analyses of LRP1 expression inmicrovessels isolated from irradiated brain as well as other measures of cerebral vasculature are in progress. Mice run in Experiment 4.1 are currently being treated with Fluvastatin and will be analyzed early in the coming grant period for amyloid plaque load and other measures related to overt Alzheimer-associated pathology. We plan to combine results from these two studies with results from Aims 1 and 2 to prepare and submit a manuscript this next grant period.

Bibliography Type: Description: (Last Updated: 03/09/2021) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings O’Banion MK, Deane R, Belcher E, Hinkle J, Dionisio-Santos D, Williams JP, Olschowka JA. "Impact of space-radiation induced alterations on toxic protein accumulation associated with neurodegenerative disease." Presented at 2018 NASA Human Research Program Investigators’ Workshop, and 29th Annual Space Radiation Investigators' Workshop, Galveston, TX, January 22-25, 2018.

Proceedings abstracts. 2018 NASA Human Research Program Investigators’ Workshop, and 29th Annual Space Radiation Investigators' Workshop, Galveston, TX, January 22-25, 2018. , Jan-2018

Abstracts for Journals and Proceedings Belcher E, Sweet T, Leffler K, Olschowka J, Williams J, O’Banion MK. "Cranial gamma irradiation impairs injury-induced microglia proliferation." 64th Annual Meeting of the Radiation Research Society, Chicago, IL, September 23-26, 2018.

Proceedings abstracts. 64th Annual Meeting of the Radiation Research Society, Chicago, IL, September 23-26, 2018. , Sep-2018

Project Title:  Impact of Space-Radiation Induced Alterations on Toxic Protein Accumulation Associated with Neurodegenerative Disease Reduce
Images: icon  Fiscal Year: FY 2018 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 01/29/2016  
End Date: 01/28/2020  
Task Last Updated: 11/24/2017 
Download report in PDF pdf
Principal Investigator/Affiliation:   O'Banion, Kerry  M.D., Ph.D. / University of Rochester 
Address:  Box 603  
601 Elmwood Ave 
Rochester , NY 14642-0001 
Email: kerry_obanion@urmc.rochester.edu 
Phone: 585-275-5185  
Congressional District: 25 
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Rochester 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Deane, Rashid  Ph.D. University of Rochester 
Majewska, Anna  Ph.D. University of Rochester 
Williams, Jacqueline  Ph.D. University of Rochester 
Key Personnel Changes / Previous PI: November 2016: There have been no changes to key personnel.
Project Information: Grant/Contract No. NNX16AE07G 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-RADIATION. Appendix D: Ground-Based Studies in Space Radiobiology 
Grant/Contract No.: NNX16AE07G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Bmed:Risk of Adverse Behavioral Conditions and Psychiatric Disorders
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
Task Description: In addition to the risk of cancer, there is concern that prolonged exposure of astronauts to deep space radiation will lead to degenerative changes in different organ systems, including the brain. Indeed we previously demonstrated that space radiation impaired cognitive performance and exacerbated Alzheimer’s disease (AD) pathology in a widely used mouse model of AD. Accumulation of the toxic peptide amyloid-ß occurs in AD and has been clearly established as an inherited cause of the disease. Space radiation at relatively modest doses elicits chronic inflammation and oxidative stress responses that alter normal brain function and may contribute to amyloid-ß accumulation by inhibiting normal clearance mechanisms. Recent data from our laboratory shows reduced clearance of amyloid-ß in mouse brain many months after exposure to space radiation. Thus, we hypothesize that radiation exacerbates Alzheimer’s disease pathology by altering the ability of the brain to remove amyloid-ß. To address this hypothesis we propose experiments that explore three possible cellular mechanisms linking radiation-induced neuroinflammation to reduced amyloid-ß clearance. We also propose to determine whether a drug that reduces brain inflammation and enhances amyloid-ß clearance can mitigate radiation-induced changes in Alzheimer’s pathology and cognitive decline in a mouse model of the disease. Taken together, these studies will lead to a better understanding of the biological mechanisms underlying risks for neurodegenerative disease after space radiation exposure.

Research Impact/Earth Benefits: Our research explores mechanisms by which toxic proteins involved in neurodegenerative diseases might accumulate in brain tissue following radiation exposure. Our results in mice using space-relevant radiation types and doses may inform about possible risks to individuals exposed to radiation on Earth whether during medical procedures or unplanned accidental exposures.

Task Progress & Bibliography Information FY2018 
Task Progress: In this second year of the grant we carried out three new irradiation campaigns. As part of NASA Space Radiation Laboratory (NSRL) NSRL-17A, we irradiated 180, 6-month old C57BL/6 male mice with different doses of silicon (10 and 50 cGy, 300 MeV/µ), iron (10 and 50 cGy, 600 MeV/µ), or 100 cGy of a modeled SPE (solar particle event) spectra of protons for Experiment 1.2. Another 108 mice served as sham controls. On April 18, 2017, we irradiated groups of 20 6-month old C57BL/6 female mice with 10 and 50 cGy Fe (600 MeV/µ) plus twenty sham controls, as an add-on experiment to assess effects on Aß clearance in females. This experiment was not part of our original proposal, but was felt to be important given our early positive findings in male mice. Because of challenges associated with our cannulation procedures, we irradiated a further set of female mice during NSRL-17C (October 24, 2017). In all cases appropriate numbers of sham-irradiated mice were similarly processed at the NSRL (e.g., placed in holders for similar times), but not exposed to radiation. All mice were shipped back to Rochester for further experiments.

Analyses completed during this grant period included Aß clearance for mice 8 and 12 months following iron irradiation (Experiment 1.1), Aß clearance for mice 4 months post-irradiation with multiple ions and doses (Experiment 1.2, see above), and Aß influx, a measure of interstitial fluid convective flow, in mice 4 and 8 months following exposure to 50 cGy 600 MeV/µ iron particles (Experiment 2.1). For studies of Aß clearance, irradiated and sham-irradiated mice were surgically implanted with a cannula into the striatum. Eighteen hours later, mice were injected via the cannula with 125l-labeled Aß1-40 and 14C-labeled inulin and sacrificed 30 min post-injection for whole brain counting of retained radioactivity. At all time points examined (4, 8, and 12 months post-irradiation with 50 cGy iron) we found clear evidence of diminished Aß clearance with radiation. This also occurred in mice irradiated with silicon or protons mimicking an SPE. From a mechanistic point, injection of antibody to LRP-1 significantly blocked clearance in control, but not irradiated mice, suggesting a defect of receptor-mediated transport of Aß across the blood brain barrier. Current studies are focused on measuring LRP-1 protein and mRNA levels in microvessels isolated from sham and irradiated mice. In contrast, we found less evidence of radiation-induced changes in convective flow: clearance of inulin from the brain was not consistently altered by radiation; moreover, direct analysis of radiolabeled Aß and inulin influx into the brain showed no changes with radiation. We also have not detected clear radiation-induced changes in astrocyte endfoot protein expression critical for regulating convective flow. Thus this passive mechanism for Aß clearance from the brain appears to be less affected by radiation than active clearance through the blood brain barrier.

Analyses related to microglial function (Aim 3) are still in process. In the coming year we will be carrying out studies using APP/PS1 transgenic mice (Aims 3 and 4).

Bibliography Type: Description: (Last Updated: 03/09/2021) 

Show Cumulative Bibliography Listing
 
 None in FY 2018
Project Title:  Impact of Space-Radiation Induced Alterations on Toxic Protein Accumulation Associated with Neurodegenerative Disease Reduce
Images: icon  Fiscal Year: FY 2017 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 01/29/2016  
End Date: 01/28/2020  
Task Last Updated: 11/28/2016 
Download report in PDF pdf
Principal Investigator/Affiliation:   O'Banion, Kerry  M.D., Ph.D. / University of Rochester 
Address:  Box 603  
601 Elmwood Ave 
Rochester , NY 14642-0001 
Email: kerry_obanion@urmc.rochester.edu 
Phone: 585-275-5185  
Congressional District: 25 
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Rochester 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Deane, Rashid  Ph.D. University of Rochester 
Majewska, Anna  Ph.D. University of Rochester 
Williams, Jacqueline  Ph.D. University of Rochester 
Key Personnel Changes / Previous PI: November 2016: There have been no changes to key personnel.
Project Information: Grant/Contract No. NNX16AE07G 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-RADIATION. Appendix D: Ground-Based Studies in Space Radiobiology 
Grant/Contract No.: NNX16AE07G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Bmed:Risk of Adverse Behavioral Conditions and Psychiatric Disorders
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
Task Description: In addition to the risk of cancer, there is concern that prolonged exposure of astronauts to deep space radiation will lead to degenerative changes in different organ systems, including the brain. Indeed we previously demonstrated that space radiation impaired cognitive performance and exacerbated Alzheimer’s disease (AD) pathology in a widely used mouse model of AD. Accumulation of the toxic peptide amyloid-ß occurs in AD and has been clearly established as an inherited cause of the disease. Space radiation at relatively modest doses elicits chronic inflammation and oxidative stress responses that alter normal brain function and may contribute to amyloid-ß accumulation by inhibiting normal clearance mechanisms. Recent data from our laboratory shows reduced clearance of amyloid-ß in mouse brain many months after exposure to space radiation. Thus, we hypothesize that radiation exacerbates Alzheimer’s disease pathology by altering the ability of the brain to remove amyloid-ß. To address this hypothesis we propose experiments that explore three possible cellular mechanisms linking radiation-induced neuroinflammation to reduced amyloid-ß clearance. We also propose to determine whether a drug that reduces brain inflammation and enhances amyloid-ß clearance can mitigate radiation-induced changes in Alzheimer’s pathology and cognitive decline in a mouse model of the disease. Taken together, these studies will lead to a better understanding of the biological mechanisms underlying risks for neurodegenerative disease after space radiation exposure.

Research Impact/Earth Benefits: Our research explores mechanisms by which toxic proteins involved in neurodegenerative diseases might accumulate in brain tissue following radiation exposure. Our results in mice using space-relevant radiation types and doses may inform about possible risks to individuals exposed to radiation on Earth whether during medical procedures or unplanned accidental exposures.

Task Progress & Bibliography Information FY2017 
Task Progress: In this first year of the grant we have carried out irradiations at NASA Space Radiation Laboratory (NSRL) for 3 of our proposed experiments. More specifically, during NSRL Run 16B, we irradiated 108, 6-month old C57BL/6 male mice with 50 cGy 600 MeV/µ iron particles on June 1, 2016 for Experiment 1.1, and irradiated another 120, 6-month old C57BL/6 male mice with different doses of silicon (10 and 50 cGy, 300 MeV/µ; May 31, 2016), iron (10 and 50 cGy, 600 MeV/µ; June 1, 2016), or 100 cGy of a modeled SPE (solar particle event) spectra of protons (June 2, 2016) for Experiment 3.1. Our team returned to Brookhaven on October 11, 2016, during NSRL Run 16C to expose 126 mice to 50 cGy of 600 MeV/µ iron particles for use in Experiment 2.1. In all cases appropriate numbers of sham-irradiated mice were similarly processed at the NSRL (e.g., placed in holders for similar times), but not exposed to radiation. All mice were shipped back to Rochester for further experiments. During these experiments, some mice were lost due to aggressive behavior within specific cages. We worked with Veterinary staff at both Brookhaven and Rochester to try and reduce the prevalence of this problem. Reducing the number of times that cages are changed at Brookhaven appeared to help reduce male aggression during NSRL 16C.

We completed our first analysis of Aß clearance, described in Experiment 1.1, in early October of this year. This represents a 4-month time point following irradiation. Irradiated (50 cGy 600 MeV/µ iron) and sham-irradiated mice were surgically implanted with a cannula into the striatum. Eighteen hours later, mice were injected via the cannula with 125l-labeled Aß1-40 and 14C-labeled inulin and sacrificed at 5 or 30 min post-injection for whole brain counting of retained radioactivity. In sham-irradiated (Control) mice injected 125I-Aß1-40 was rapidly cleared from brain, with 37% remaining after 30 min. In contrast, this clearance was significantly diminished with 61% remaining in brain after 30 min in irradiated mice. From a mechanistic point, injection of antibody to LRP-1 significantly blocked clearance in control, but not irradiated mice, suggesting a defect of receptor-mediated transport of Aß across the blood brain barrier. Clearance of inulin was also affected by radiation: there was a significant decline in 14C-Inulin after 30 min in control mice that was completely absent in irradiated mice. These results replicate previous data with C57BL/6 mice 10 months after irradiation with 50 cGy iron particles. Additional analyses of these same mice will be carried out at 8 and 12 months of age to complete Experiment 1.1.

Analyses of mice irradiated 6 months ago with multiple ions to examine microglial function will be carried out in December 2016 (Experiment 3.1) and mice irradiated with iron will be available to start gathering data related to Experiment 2.1 (CSF clearance) in February 2017.

Bibliography Type: Description: (Last Updated: 03/09/2021) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings O’Banion MK, Belcher E, Duclos L, Hinkle J, Olschowka JA, Williams JP. "Impact of Space Radiation Induced Neuroinflammation on Alzheimer and Parkinson Disease Pathology." Presented at 2016 NASA Human Research Program Investigators’ Workshop, and 27th Annual Space Radiation Investigators' Workshop, Galveston, TX, February 8-11, 2016.

2016 NASA Human Research Program Investigators’ Workshop, and 27th Annual Space Radiation Investigators' Workshop, Galveston, TX, February 8-11, 2016. , Feb-2016

Abstracts for Journals and Proceedings O’Banion MK, Deane R, Majewska A, Williams JP, Olschowka JA. "Impact of Space-Radiation Induced Alterations on Toxic Protein Accumulation Associated with Neurodegenerative Disease." Presented at 2016 NASA Human Research Program Investigators’ Workshop, and 27th Annual Space Radiation Investigators' Workshop, Galveston, TX, February 8-11, 2016.

2016 NASA Human Research Program Investigators’ Workshop, and 27th Annual Space Radiation Investigators' Workshop, Galveston, TX, February 8-11, 2016. , Feb-2016

Abstracts for Journals and Proceedings O’Banion MK, Deane R, Majewska A, Williams JP, Olschowka JA. "Impact of Space-Radiation Induced Alterations on Toxic Protein Accumulation Associated with Neurodegenerative Disease." Presented at 2017 NASA Human Research Program Investigators’ Workshop, and 28th Annual Space Radiation Investigators' Workshop, Galveston, TX, January 23-26, 2017.

2017 NASA Human Research Program Investigators’ Workshop, and 28th Annual Space Radiation Investigators' Workshop, Galveston, TX, January 23-26, 2017. , Jan-2017

Project Title:  Impact of Space-Radiation Induced Alterations on Toxic Protein Accumulation Associated with Neurodegenerative Disease Reduce
Images: icon  Fiscal Year: FY 2016 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 01/29/2016  
End Date: 01/28/2020  
Task Last Updated: 03/15/2016 
Download report in PDF pdf
Principal Investigator/Affiliation:   O'Banion, Kerry  M.D., Ph.D. / University of Rochester 
Address:  Box 603  
601 Elmwood Ave 
Rochester , NY 14642-0001 
Email: kerry_obanion@urmc.rochester.edu 
Phone: 585-275-5185  
Congressional District: 25 
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Rochester 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Deane, Rashid  Ph.D. University of Rochester 
Majewska, Anna  Ph.D. University of Rochester 
Williams, Jacqueline  Ph.D. University of Rochester 
Project Information: Grant/Contract No. NNX16AE07G 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-RADIATION. Appendix D: Ground-Based Studies in Space Radiobiology 
Grant/Contract No.: NNX16AE07G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:  
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Bmed:Risk of Adverse Behavioral Conditions and Psychiatric Disorders
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
Task Description: In addition to the risk of cancer, there is concern that prolonged exposure of astronauts to deep space radiation will lead to degenerative changes in different organ systems, including the brain. Indeed we previously demonstrated that space radiation impaired cognitive performance and exacerbated Alzheimer’s disease (AD) pathology in a widely used mouse model of AD. Accumulation of the toxic peptide amyloid-ß occurs in AD and has been clearly established as an inherited cause of the disease. Space radiation at relatively modest doses elicits chronic inflammation and oxidative stress responses that alter normal brain function and may contribute to amyloid-ß accumulation by inhibiting normal clearance mechanisms. Recent data from our laboratory shows reduced clearance of amyloid-ß in mouse brain many months after exposure to space radiation. Thus, we hypothesize that radiation exacerbates Alzheimer’s disease pathology by altering the ability of the brain to remove amyloid-ß. To address this hypothesis we propose experiments that explore three possible cellular mechanisms linking radiation-induced neuroinflammation to reduced amyloid-ß clearance. We also propose to determine whether a drug that reduces brain inflammation and enhances amyloid-ß clearance can mitigate radiation-induced changes in Alzheimer’s pathology and cognitive decline in a mouse model of the disease. Taken together, these studies will lead to a better understanding of the biological mechanisms underlying risks for neurodegenerative disease after space radiation exposure.

Research Impact/Earth Benefits:

Task Progress & Bibliography Information FY2016 
Task Progress: New project for FY2016.

Bibliography Type: Description: (Last Updated: 03/09/2021) 

Show Cumulative Bibliography Listing
 
 None in FY 2016