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

Coninx Emma

Promoter

Moons Lieve, (KULeuven), lieve.moons@bio.kuleuven.be

SCK•CEN Mentor

Verslegers Mieke
mieke.verslegers@sckcen.be
+32 14 33 28 67

SCK•CEN Co-mentor

Quintens Roel
roel.quintens@sckcen.be
+32 14 33 28 37

Expert group

Radiobiology

PhD started

2016-10-01

Short project description

Epidemiological and animal studies increasingly recognize the harmful effects of ionizing radiation, even at low doses. Such health effects not only entail the increased risk of developing cancer, but also include non-cancer effects. Intriguingly, long-term radiation-induced changes seem to share several similarities with ageing, defined by chronic oxidative stress, apoptosis, inflammation, and genetic instability among others. Indeed, an association between radiation exposure and ageing or premature senescence is now evidenced and becoming well documented (Hernandez et al., 2015). As ageing is often accompanied with a loss of memory, dementia and a higher risk of developing neurodegenerative diseases such as Alzheimer disease (AD), a strong interest in studying the effect of radiation on ageing of the brain is emerging. For example, cognitive impairment and dementia is commonly observed in patients that received cranial radiotherapy earlier in life (Zhang et al., 2015), while animal data could corroborate a premature senescence, defined by chronic oxidative stress and inflammation, in irradiated brain tissue (Suman et al., 2013; Poulose et al., 2011). Interestingly, a study by Lowe et al. (2009) and results obtained at SCK•CEN (Verreet et al., unpublished data) suggested remarkable similarities in transcriptional response in the ageing and irradiated mouse brain, and proposed a potential link with AD-related genes.

Despite the current awareness, major drawbacks in this field are the inconclusive epidemiological data, probably resulting from the lack of large-scale studies, and the insufficient knowledge on low-dose radiation exposure, which is a growing health concern for our society. Besides, the effect of radiation to the developing brain, for example during early childhood, remains largely elusive and needs to be actively explored. Therefore, this project will focus on different radiation doses, ranging from low-dose diagnostic to high-dose radiotherapy doses, administered to young mice predisposed to developing an AD-like phenotype, after which various ageing parameters will be investigated via a multidisciplinary approach.

 

References

Hernandez, L., M. Terradas, J. Camps, M. Martin, L. Tusell and A. Genesca (2015). "Aging and radiation: bad companions." Aging Cell 14(2): 153-161

Lowe, X. R., S. Bhattacharya, F. Marchetti and A. J. Wyrobek (2009). "Early brain response to low-dose radiation exposure involves molecular networks and pathways associated with cognitive functions, advanced aging and Alzheimer's disease." Radiat Res 171(1): 53-65.

Poulose, S. M., D. F. Bielinski, K. Carrihill-Knoll, B. M. Rabin and B. Shukitt-Hale (2011). "Exposure to 16O-particle radiation causes aging-like decrements in rats through increased oxidative stress, inflammation and loss of autophagy." Radiat Res 176(6): 761-769.

Suman, S., O. C. Rodriguez, T. A. Winters, A. J. Fornace, Jr., C. Albanese and K. Datta (2013). "Therapeutic and space radiation exposure of mouse brain causes impaired DNA repair response and premature senescence by chronic oxidant production." Aging (Albany NY) 5(8): 607-622.

Zhang, L., H. Yang and Y. Tian (2015). "Radiation-induced cognitive impairment." Therapeutic Targets for Neurological Diseases 2(2).

 

Objective

In this project, we will use a transgenic AD mouse model, characterized by a temporal- and region-specific amyloid-beta (Aβ) and tau pathology and by functional memory deficits, which closely resemble the disease phenotype in AD patients. Young postnatal mice will be subjected to low and high doses of X-rays, after which the onset of ageing and AD hallmarks such as an impaired neurogenesis and neurodegeneration will be investigated via various immunohistochemical and protein analyses. At the functional level, mice will be subjected to a cognitive test battery at different ages, assessing memory-related functions that are typically impaired during AD progression (in collaboration with the Laboratory of Biological Psychology, Prof. Rudi D'Hooge, KU Leuven).

In a second part of the project, we will aim to better understand the cellular events that underlie a possible premature ageing following irradiation. For this, we will use a hippocampal cell culture that was previously optimized in our lab, and which mimics ageing of single neurons within a limited time span. Cells will be irradiated at an early time point, defined by neuronal maturation and network formation and corresponding to early postnatal brain development. Afterwards, cellular ageing, defined by e.g. mitochondrial dysfunction, ROS production and cell death, will be investigated.

Finally, to dissect the molecular changes and to identify key players responsible for a radiation-induced ageing, we will perform a high-throughput gene expression analysis on brain tissue derived from AD mice and on long-term cultured neurons subjected to a range of X-ray doses. Molecules of interest will be subsequently validated with qPCR, Western blotting and immunohistochemical techniques. Of interest, such experiments might possibly identify new ageing biomarkers for children exposed to diagnostic X-rays or undergoing radiotherapy to the head.