Impact of chronic astrocytic interleukin-6 overexpression on behaviour and mRNA expression and effects of a phytosomal curcumin diet in mice

Abstract

Neuroinflammation is a physiological and well-organized response in which astrocytes and microglia can be stimulated and secrete pro- and/or anti-inflammatory molecules. This balanced response neutralizes harmful stimuli while limiting damage of neuronal cell. Neuroinflammation is also the common feature of neurodegenerative diseases where it is established as a chronic process and is found in many psychiatric disorders. Neuroinflammation impacts millions of individuals globally, underscoring the importance of comprehensively understanding this mechanism as a promising therapeutic target. Curcumin is a natural anti-inflammatory compound that present with a remarkable therapeutical potential while current non-steroidal anti-inflammatory drugs demonstrated minimal success.

MC diet appeared to improve grip strength, specifically in 13M HET GFAP-IL6 male mice, but failed to rescue motor behaviour in 4M or 8M HOM GFAP-IL6 mice. It also seemed to promote locomotor activity and reduce anxiety-like behaviour in 13M male HET GFAP-IL6 and WT-like mice. A hypo-locomotor effect of MC diet was observed in female HOM GFAP-IL6 and WT-like mice at 4M and 8M. MC feeding had various consequences on gene expression based on the genotype, sex and brain area considered, modifying gene expression mainly in the hippocampus for 14M HET GFAP-IL6 and WT-like mice, while mostly changing it in the amygdala for 9M HOM GFAP-IL6 and WT-like mice. The transcriptomic effect of MC diet often reinforced the genotype effect associated with astrocytic IL-6 overexpression.

Decreased anxiety-like and impaired motor behaviour emerged as a consistent phenotype of GFAP-IL6 mice but may be masked by ageing in mice with mild astrocytic IL-6 overexpression or revealed from a younger age in mice with high astrocytic IL-6 overexpression. All studied brain areas showed signs of increased microglial and astrocytic reactivity. However, expression of neuroinflammatory and neurotransmission related mRNA varied in number and nature depending on the region considered but also genotype and sex. This suggests that IL-6 overexpression does not affect the brain uniformly in the GFAP-IL6 mice which might underlie diverse behavioural outcomes. Long-term MC diet showed various effects based on the test and, the sex and genotype of the mice. Our results suggest that curcumin could be beneficial against cognitive and motor decline in ageing mice and can modulate proinflammatory mechanisms. However, curcumin might not be the best therapeutical option to interfere with IL-6 overexpression in our model as they might both upregulate the same type of markers.

Date of Thesis submission	2024
Original language	English
Awarding Institution	Western Sydney University
Supervisor	Erika Gyengesi Bilaver (Supervisor), Rose Chesworth Vieyra (Supervisor), Tim Karl (Supervisor), Gerald Muench (Supervisor), Anand Hardikar (Supervisor), Mugdha Joglekar (Supervisor) & Garry Niedermayer (Supervisor)