Does C3-deficiency alter the amyloid precursor protein expression and thalamic structure following cranial radiotherapy to the developing brain?

Abstract

Abstract Brain tumours in children preserve certain characteristics of the original stem cells that develop during foetal life. How do cancer cells acquire these characteristics is unknown. New research suggests that cell origin and its genetic alterations play a huge role in tumour development, tumour aggressiveness and prognosis. It is well known that more than 70 % of brain tumours in children can be cured with cranial radio-therapy (CRT) in combination with chemotherapy and/or surgery. Thereby, CRT is an effective cornerstone of the treatment of paediatric brain tumours but it also causes severe chronic adverse effects, such as neurocognitive decline. It is believed that CRT causes acute neuro-inflammation that making it difficult for the brain to heal and thereby disturbs the plasticity of the brain. C3 is an influential component of the complement system. Several previous studies highlighted the importance of C3 in both foetal and adult neurogenesis as it has an immune-dependent ability to protect/repair damaged cells and removal of damaged synapses in the brain. It has also been shown that mice lacking C3 have a better cognitive outcome following cranial radio-therapy (CRT). The part of the brain called the thalamus is a collection of relay stations with extraordinary function between the senses in our body, and our reaction to these senses via the cortical and subcortical brain and it rich in APP-cells. Amyloid precursor protein (APP) is an integral membrane protein expressed in many tissues, including the thalamus. APP has been shown to have an important role as a regulator of synapse formation and modulation of neural plasticity (memory and learning ability). This project used wild type mice and mice lacking C3 to highlight how CRT will affect the thalamus and its synaptic functions. Also, four groups were used in this study; control wild type, CR-treated wild type, control C3-genmodified and CR-treated C3-genmodified (C3-/-) mice. Significant reduction in the volume of the thalamus was noted following CRT in both wild type and C3-genmodified mice. The expression of APP in the thalamus appears to be preserved in spite of CRT in both wild type and C3-genmodified mice. We conclude that modulating the immune system did not protect the thalamus from CRT-induced injury. In addition, C3-defiicency (C3-/-) did not alter the APP expression in this region. The protection of memory function seen in C3-deficient (C3-/-) mice after CRT must therefore depend on another region in the brain.