Ageing biomarkers in the brain : exploring stress effects in traditional and non-traditional model systems

Abstract

Ageing is a complex mechanism influenced by multiple factors. Stress, which could affect ageing, is mainly controlled by the hypothalamus-pituitary-adrenal (HPA)-axis and subsequent glucocorticoid (GC) release. Increases in GCs also induce long-lasting developmental changes in the organism (i.e. GC developmental programming), which may, in turn, affect brain ageing processes.

This thesis aimed to determine the effects of stress on the brain by examining ageing biomarkers using both in-vitro and in-vivo approaches. In Chapter 2, the effects of stress biomarkers (GCs and alpha-amylase) were explored at cellular level, using HT22 (murine hippocampal neuronal cells). Within physiological concentrations, cortisol, but not corticosterone, showed a potential protective effect. Moreover, alpha-amylase protected cells against additional stressors, suggesting that increased stress biomarkers maintained cellular viability, instead of affecting senescent phenotypes.

In Chapter 3, the typical mammalian brain ageing phenotypes were characterised in Japanese quail (Coturnix japonica) prior to investigating prenatal GC programming. Increased oxidative damage accumulation and changes in adult neurogenesis were found. Contrastingly, neuronal loss and increased white matter lesions were not observed.

Chapter 4 investigated the prenatal GC programming effect in juvenile quail brains. Prenatal stress reduced glucocorticoid receptor expression in the amygdala and nidopallium, indicating prenatal GC programming; however, oxidative damage accumulation was unaffected.

In Chapter 5, the prenatal GC programming effect was examined on both the stress response and neurogenesis in adult quails. Prenatal stress resulted in higher peak stress responses and increased neurogenesis, suggesting that it maintained high neuronal plasticity rather than enhancing typical ageing phenotypes.

In conclusion, although ageing phenotypes are not necessarily conserved, comparative animal models can aid the investigation of human brain ageing. Stress may indirectly affect ageing via other systems. Therefore, investigating brain ageing at the system level should be considered as an alternative to focusing on single biomarkers in future.