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
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