Name: Emma Coninx
Date: October 2, 2020
Venue: KU Leuven
The risks of early-life X-ray exposure: A view on brain aging and Alzheimer’s disease pathology
Aging entails a progressive decline in functional capacity of various cells and organs, which can result in many aging-associated diseases, including dementia. The most common form of dementia is Alzheimer’s disease (AD), associated with a high societal and economic burden. The prevalence of such age-related diseases is expected to rise due to the strong increase in life expectancy seen in developed countries. Therefore, it is important to identify potential risk factors for aging, as well as AD. In fact, based on the high overlap in their hallmarks, ionizing radiation is proposed as a potential risk factor for premature aging.
The developing brain of children is especially sensitive to effects of radiation, which is evidenced by the occurrence of neurological side effects following cranial radiotherapy. Therefore, to further evaluate the long-term risks associated with radiation exposure, we set out to examine if X-ray exposure of the developing brain could result in accelerated aging, thereby increasing the risk for developing AD pathology, making use of a triple transgenic Alzheimer mouse model (3xTg). Apart from radiation-induced DNA damage and oxidative stress, we found an acceleration of the age-associated decline in hippocampal neurogenesis upon 1.8 Gy-irradiation. Although irradiated 3xTg-AD mice did not show changes in hippocampal-dependent learning and memory with increasing age, synaptic plasticity was impaired and the AD pathology (expression of tau fibrils and amyloid-β aggregates) was aggravated when compared to non-irradiated AD mice. Based on radiation-induced effects observed in healthy C57BL/6J mice, we could further suggest a reactivation of astrocytes and microglia in the aged irradiated brain. In addition, decreased contextual learning was observed, which might be suggestive for some hippocampal-dependent cognitive decline in non-exposed healthy mice. To measure whether biological age was also increased following irradiation, we developed epigenetic clocks specific for mouse hippocampus and cortex. However, irradiation did not alter the biological age and might thus not influence epigenetic aging in these brain tissues.
In conclusion, we extended the follow-up time in which aging hallmarks induced by early-life X-ray exposure were investigated and were able to identify an associated risk for hippocampal aging. Such an accelerated aging is further proposed to foster AD pathology in predisposed individuals, independent of epigenetic alterations.
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