Dottorato in BIOCHIMICA

Titolo della tesi: Sex-dependent Brain-specific Alterations of Insulin Signalling Uncover Early Molecular Mechanisms Leading to Cognitive Decline

This project will clarify the molecular mechanisms involved in the onset of brain insulin resistance (bIR). Physiologically, the insulin signalling (IS) regulates the maintenance of synaptic plasticity, the cell stress response and the neuronal metabolism, which are processes central to cognitive and learning functions. A novel mediator of the IS, the enzyme biliverdin reductase A (BVR-A), which we believe to be one of the proteins first impaired along the development of brain IR. To achieve this goal, we will administer a high-fat diet (HFD) to C57Bl/6j mice divided into female and male, which promotes several molecular changes in the brain by promoting the onset of brain IR. By following the temporal profile of these alterations, we will be able to define when the dysfunction of BVR-A occurs. To strengthen the role of BVR-A we will perform the same experiments in mice in which BVR-A has been genetically deleted. Results from this part will answer to the question whether the lack of BVR-A favours the onset of brain IR. Our results show that HFD induced peripheral metabolic alterations and cognitive dysfunctions at each time points. Intriguingly, 1 week of diet is enough to promote a reduction of BVR-A levels in the brain. In fact, the activation of brain insulin signalling is impaired in frontal cortex of male and female mice fed with HFD. Sex-differences observed in the frontal cortex can be also noticed in the hippocampus. However, it seems that the alterations of the signalling occur later in the hippocampus than the frontal cortex, particularly in female mice. The observed alterations are further corroborated by measures of cognitive functions. Female and male mice show that frontal cortex inputs improve both behavioural performance and neural encoding for objects when recognition is difficult. Lack of BVR-A seems to be implicated in the observed alterations considering that similar results have been collected in knock-out mice. Overall, our data suggest that loss of BVR-A is among the first events that can be observed during the development of bIR. Reduced BVR-A protein levels produce different effects on insulin signalling considering that BVR-A is a crucial player at different levels both upstream and downstream in the pathway. The comprehension of the initiating molecular events leading to brain IR is fundamental to develop new prevention strategies aimed to reduce the risks and the negative impact of metabolic alterations in the brain.