Space-Like Irradiation Exacerbated Cognitive Deficits and Amyloid Pathology in CRND8 Mouse Model of Alzheimer’s Disease

Article type: Research Article

Authors: Wang, Wenzhang^{a; 1} | Zhao, Fanpeng^{a; 1} | Torres, Sandy^a | Harris, Peggy L.R.^b | Wang, Xinglong^c | Peng, Lihua^a | Siedlak, Sandra L.^a | Zhu, Xiongwei^{a; *}

Affiliations: [a] Department of Pathology, Case Western Reserve University, Cleveland, OH, USA | [b] Department of Genetics, Case Western Reserve University, Cleveland, OH, USA | [c] Department of Pharmacology & Toxicology, University of Arizona, Tucson, AZ, USA

Correspondence: [*] Correspondence to: Xiongwei Zhu, PhD, Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH 44106, USA. E-mail: xiongwei.zhu@case.edu.

Note: [1] These authors contributed equally to this work.

Abstract: Background:Space radiation was linked to neurological damage and behavioral deficits which raised concerns of increased degenerative risk on the brain and development of Alzheimer’s disease following space travel. Objective:In this study, we investigated the effects of irradiation by 56Fe and 28Si in CRND8 mice, an Alzheimer’s disease mouse model. Methods:Six-month-old CRND8 mice were exposed to whole body irradiation by 56Fe and 28Si at 0.5 Gy and 2 Gy doses. Behavior tests were administered 1-month to 3-months post-irradiation. Amyloid deposition and other pathological changes were analyzed 3-months and/or 6-months post-irradiation. Results:The Novel Object Recognition test showed some decline in 8-month-old mice compared to non-irradiated CRND8 mice. Male mice also showed a loss of freezing behavior in the fear conditioning contextual test following irradiation. Golgi staining revealed a loss of spines in hippocampal neurons after irradiation. Total amyloid immunohistochemistry showed a robust increase in 3-months post-irradiation 56Fe groups which became normalized to non-irradiated group by 6-months post-irradiation. However, 2 Gy 28Si caused a trend towards increased plaque load at 3-months post-irradiation which became significant at 6-months post irradiation only in male CRND8 mice. While 0.5 Gy Fe did not induce obvious changes in the total number of iba-1 positive microglia, more hippocampal microglia were found to express PCNA after 0.5 Gy Fe treatment, suggesting potential involvement of microglial dysfunction. Conclusions:Overall, our study provides new evidence of gender-specific and ion-dependent effects of space radiation on cognition and amyloid pathology in AD models.

Keywords: Alzheimer’s disease, microglia, PCNA, senescence, space radiation

DOI: 10.3233/JAD-240570

Journal: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S327-S339, 2024