Chronic low-dose-rate ionising radiation affects the hippocampal phosphoproteome in the ApoE-/- Alzheimer's mouse model.

// Stefan J. Kempf 1, 2 , Dirk Janik 3 , Zarko Barjaktarovic 1 , Ignacia Braga-Tanaka III 4 , Satoshi Tanaka 4 , Frauke Neff 3 , Anna Saran 5 , Martin R. Larsen 2 , Soile Tapio 1 1 Institute of Radiation Biology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health GmbH, Neuherberg, Germany 2 Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark 3 Institute of Pathology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health GmbH, Neuherberg, Germany 4 Institute for Environmental Sciences, Rokkasho, Japan 5 Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l´Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy Correspondence to: Stefan J. Kempf, email: stefank@bmb.sdu.dk Soile Tapio, email: soile.tapio@helmholtz-muenchen.de Keywords: synaptic plasticity, hippocampus, dendritic spine, synapse, phosphoproteomics Received: August 12, 2016      Accepted: September 20, 2016      Published: September 30, 2016 ABSTRACT Accruing data indicate that radiation-induced consequences resemble pathologies of neurodegenerative diseases such as Alzheimer´s. The aim of this study was to elucidate the effect on hippocampus of chronic low-dose-rate radiation exposure (1 mGy/day or 20 mGy/day) given over 300 days with cumulative doses of 0.3 Gy and 6.0 Gy, respectively. ApoE deficient mutant C57Bl/6 mouse was used as an Alzheimer´s model. Using mass spectrometry, a marked alteration in the phosphoproteome was found at both dose rates. The radiation-induced changes in the phosphoproteome were associated with the control of synaptic plasticity, calcium-dependent signalling and brain metabolism. An inhibition of CREB signalling was found at both dose rates whereas Rac1-Cofilin signalling was found activated only at the lower dose rate. Similarly, the reduction in the number of activated microglia in the molecular layer of hippocampus that paralleled with reduced levels of TNFα expression and lipid peroxidation was significant only at the lower dose rate. Adult neurogenesis, investigated by Ki67, GFAP and NeuN staining, and cell death (activated caspase-3) were not influenced at any dose or dose rate. This study shows that several molecular targets induced by chronic low-dose-rate radiation overlap with those of Alzheimer´s pathology. It may suggest that ionising radiation functions as a contributing risk factor to this neurodegenerative disease.