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, 7 (12), e53275

Galactic Cosmic Radiation Leads to Cognitive Impairment and Increased Aβ Plaque Accumulation in a Mouse Model of Alzheimer's Disease

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Galactic Cosmic Radiation Leads to Cognitive Impairment and Increased Aβ Plaque Accumulation in a Mouse Model of Alzheimer's Disease

Jonathan D Cherry et al. PLoS One.

Abstract

Galactic Cosmic Radiation consisting of high-energy, high-charged (HZE) particles poses a significant threat to future astronauts in deep space. Aside from cancer, concerns have been raised about late degenerative risks, including effects on the brain. In this study we examined the effects of (56)Fe particle irradiation in an APP/PS1 mouse model of Alzheimer's disease (AD). We demonstrated 6 months after exposure to 10 and 100 cGy (56)Fe radiation at 1 GeV/µ, that APP/PS1 mice show decreased cognitive abilities measured by contextual fear conditioning and novel object recognition tests. Furthermore, in male mice we saw acceleration of Aβ plaque pathology using Congo red and 6E10 staining, which was further confirmed by ELISA measures of Aβ isoforms. Increases were not due to higher levels of amyloid precursor protein (APP) or increased cleavage as measured by levels of the β C-terminal fragment of APP. Additionally, we saw no change in microglial activation levels judging by CD68 and Iba-1 immunoreactivities in and around Aβ plaques or insulin degrading enzyme, which has been shown to degrade Aβ. However, immunohistochemical analysis of ICAM-1 showed evidence of endothelial activation after 100 cGy irradiation in male mice, suggesting possible alterations in Aβ trafficking through the blood brain barrier as a possible cause of plaque increase. Overall, our results show for the first time that HZE particle radiation can increase Aβ plaque pathology in an APP/PS1 mouse model of AD.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Effect of 56Fe particle radiation on memory and cognition using contextual fear conditioning and novel object recognition tests.
(A) Fear conditioning results quantified as percent time freezing. (B) No significant difference was found between any groups in freezing to a novel context or a tone stimulus. (C) Novel object recognition test using the recognition index generated for time spent with the novel object. All data is compared within the respective gender. Data was analyzed with Student’s t-test for the females and one-way ANOVA with a Bonferroni post test for the males. Graphs show means ± SD, n = 8–14 animals per condition at each dose. **P<.01, ***P<.001.
Figure 2
Figure 2. Immunohistochemical staining for Congo red and 6E10 increases after 56Fe particle irradiation.
(A, C) Representative images of half male brains stained for Congo red (A) or 6E10 (C) 6 months after 0 cGy or 100 cGy 56Fe particle radiation. Scale bar is 1 mm. (B, D) Quantitative measurement of percent plaque area assessed with Congo red (B) and 6E10 (D). In addition, total number of individual 6E10 positive plaques (E) and the average size of plaques (µm2) (F) was determined. Each dot represents a single animal measured as percent area of the cortex and hippocampus combined. Data was analyzed with Student’s t-test for the females and one-way ANOVA with a Bonferroni post test for the males. Data displayed as mean ± SD, n = 8–14 animals per dose. *P<.05, **P<.01.
Figure 3
Figure 3. Radiation increases select Aβ isoforms but has no effect on APP processing.
Dot plot analysis of soluble Aβ40 (A), Aβ42 (B) and insoluble Aβ40 (C) and Aβ42 (D). Each dot represents one animal. Data was analyzed with Student’s t-test for the females and one-way ANOVA with a Bonferroni post test for the males. (E, F) Male 0 cGy and 100 cGy APP (E) and β-C terminal fragment (F) protein levels were measured via Western blot and standardized to α-tubulin. Representative images of blots are present in E’ and F’. Results were analyzed with Student’s t-test. Data displayed as mean ± SD, n = 8–14 animals per dose. *P<.05, **P<.01.
Figure 4
Figure 4. There is no change in glial activation after 56Fe particle irradiation.
(A) CD68 area was normalized to individual plaque area to account for differences in plaque size. 12 plaques in each mouse were analyzed and averaged together to compare male control and 100 cGy irradiated mice. (B) CD68 was also normalized to the total Iba-1 microglia area around the plaque to account for potential changes in microglia number. (C) Iba-1 area was standardized to plaque area. Each dot represents a single animal. (D) Visual representation of CD68/Iba-1 staining around a plaque. Images acquired at 40x magnification, scale bar is 5 µm. (E) Representative hippocampal images taken to demonstrate Iba-1+ microglial morphology. Images acquired at 20x magnification, scale bar is 10 µm. (F) Astrocyte activation was measured using GFAP percent area measurements in the cortex (n = 4–5 mice per dose). (G) Insulin Degrading Enzyme (IDE) protein level was measured and quantified via Western blot analysis. IDE levels were normalized against α-tubulin as a loading control (n = 7 mice per dose). Representative images are shown in G’. (H) Protein levels of TNFα were quantified via ELISA. Data is presented as mean ± SD. The results were analysed with Student’s t test, n = 13–14 mice per dose in A, B, C and H.
Figure 5
Figure 5. 56Fe particle radiation causes endothelial activation.
(A) Representative images of ICAM-1 staining. Pictures are at 20x magnification and the scale bar is 10 µm. (B) ICAM-1 area was measured as percent total area in the entire cortex in 2 serial sections with the results being averaged together. Each dot represents a single animal. (C) Protein samples were analyzed for LRP1 using Western blot. LRP1 levels were standarized against α-tubulin as a loading control. Representative immunoblot image is present in C’. Data is presented as mean ± SD. Results were analysed with a Student’s t-test. n = 13–14 animals per dose.

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