title: Chronic low-dose-rate ionising radiation affects the hippocampal phosphoproteome in the ApoE-/- Alzheimer's mouse model.
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.
authors.affiliation: Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.|Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Kempf
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Janik
authors.affiliation: Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.
authors.forename: Zarko
authors.initials: Z
authors.lastname: Barjaktarovic
authors.affiliation: Institute for Environmental Sciences, Rokkasho, Japan.
authors.forename: Ignacia
authors.initials: I
authors.lastname: Braga-Tanaka
authors.affiliation: Institute for Environmental Sciences, Rokkasho, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Neff
authors.affiliation: Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l´Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Saran
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Larsen
authors.affiliation: Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.
authors.forename: Soile
authors.initials: S
authors.lastname: Tapio
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000528:radiation effects*; D015227:Lipid Peroxidation / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000528:radiation effects; D009473:Neuronal Plasticity / Q000528:radiation effects; D010766:Phosphorylation; D020543:Proteome; D011829:Radiation Dosage; D011839:Radiation, Ionizing; D015398:Signal Transduction
chemical_list: D001057:Apolipoproteins E; D017362:Cyclic AMP Response Element-Binding Protein; D020543:Proteome
keywords: dendritic spine; hippocampus; phosphoproteomics; synapse; synaptic plasticity