This project will clarify the molecular mechanisms involved in the onset of brain insulin resistance (IR) and its impact on Alzheimer disease (AD) neuropathology development. AD pathogenesis is complex and beyond amyloid hypothesis, AD has a "metabolic face" mediated by impairment of brain insulin signaling (IS), known as brain IR. Physiologically, the IS regulates the maintenance of synaptic plasticity, the cell stress response and the neuronal metabolism, which are processes central to cognitive and learning functions. Therefore, brain IR is thought to play a pivotal role in AD. However, there is still a substantial lack of knowledge on how brain IR develops. Our challenge is to "fill the gap" by dissecting the role of a novel mediator of the insulin signaling, 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 feed C57Bl/6j mice a high fat diet (HFD), that promotes several molecular changes in the brain favoring the onset of brain IR and AD-like neuropathology. 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 favors the onset of brain IR. Finally, HFD-treated mice will be treated with a peptide, which by stimulating BVR-A activity, should improve brain IS and thus recover mice from brain IR. The comprehension of the initiating molecular events leading to brain IR in AD is fundamental to develop new prevention strategies aimed to reduce the risks and the negative impact of metabolic alterations in the brain. BVR-A could become a novel therapeutic target with the potential to significantly impact on a big portion of the population with positive social and economic outcomes.
