Identification of radiation-induced premature ageing and neurodegeneration in a mouse model for Alzheimer’s disease.

SCK•CEN Mentor

Coninx Emma, econinx@sckcen.be, +32 (0)14 33 27 59

Expert group

Radiobiology

SCK•CEN Co-mentor

Verslegers Mieke , mversleg@sckcen.be , +32 (0)14 33 28 67

Introduction

Nowadays, hot topic for many research groups is finding treatment options for the complex and progressive neurodegenerative disorder, Alzheimer’s disease (AD). Equally important, however, is finding the initial inducers of AD, which remain largely elusive and is often subject to debate. The major risk factor for AD is unarguable aging, which is proposed to be accelerated by ionizing radiation exposure. In the medical field, the increasing usage of high-dose radiation beams for cancer therapy raises concerns about their potential adverse effects. Epidemiological and animal studies have shown that the developing, immature brain is more sensitive to ionizing radiation exposure compared to the adult brain. This is illustrated by a decreased intelligence and cognition in cancer survivors who underwent cranial radiotherapy during childhood, with early age at exposure being the prime determinant. Despite the clear common features between radiation-induced changes and an aging phenotype in the CNS, the mechanisms of childhood irradiation to induce aging, and possibly AD, still need to be explored.

Objective

To this end, we will use as a triple transgenic (3xTg-AD) mouse model predisposed to AD, in which aging and AD progression after early-life X-ray exposure can be studied within a limited time span. After exposure of ten-day-old mice to clinically relevant X-ray doses, the cellular effects of ionizing radiation, neuronal dysfunction in the hippocampus and hippocampal-dependent cognitive decline will be evaluated at 3, 6 and 12 months of age. With fluorescence microscopy of brain slices, we will evaluate adult neurogenesis, DNA damage and amyloid-β and p-tau pathology. Moreover, oxidative stress and inflammation will be examined, respectively with western blot and flow cytometry. Finally a behavioral test battery, including a Morris water maze and elevated plus maze, will give us more insights into hippocampal cognitive decline. The in vivo work will be complemented with analyses of in vitro aged (sham-) irradiated primary mouse hippocampal neurons. Before assessing the radiation impact, hippocampal aging processes will be characterized by assessing DNA damage, oxidative stress and neuronal network connectivity, which will be complemented with a real-time follow-up of cellular senescence and identification of specific aging hallmarks through Western blotting experiments. Except for the behavioral tests (KU Leuven), all experiments will be performed at the nuclear research center SCK•CEN in Mol.

 

Techniques:

Based on the time of the internship and in consultation with the student’s interest, the student will either work on the in vitro or in vivo part.

  • The in vivo part consists out of mouse brain dissection, cryosectioning, histology, immunostainings, fluorescence microscopy, protein extraction, western blot, microglial isolation, flow cytometry and (potentially) behavioral tests.
  • The in vitro part consist out of primary hippocampal neuron culture, immunostainings, fluorescence microscopy, protein extraction, western blot and Incucyte assays.
     
     

The minimum diploma level of the candidate needs to be

Academic bachelor

The candidate needs to have a background in

Biology , FELASA cat B

Estimated duration

9 maanden