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.
With a long prodromal period of 10 to 20 years, AD and related dementia are becoming a priority for many governments, considering that 1% of global gross domestic product is spent on dementia care. bIR greatly contributes to this preclinical period during which only subtle behavioral symptoms are evident. Moreover, no reliable biomarkers indicative of a potential risk are available. Hence, the comprehension of the initiating molecular events leading to bIR is fundamental to enhance development of new prevention strategies aimed to reduce both the risks and the outcomes of metabolic dysfunctions in the brain.
The proposed research is innovative because it focuses on an entirely new paradigm in which reduced BVR-A activation could represent a novel marker to predict early alterations of IS, possibly leading to bIR in AD. The ground-breaking nature of this project will ¿fill this gap¿ by clarifying a novel biological mechanism underlying early alterations of the insulin signalling cascade. We suggest that the evaluation of the activation state of biliverdin reductase-A (BVR-A) protein could be of help for unraveling ¿unknown mechanisms¿ occurring during the pathological stages that precedes the onset of insulin resistance both in the brain and in the peripheral tissues. Consequently, BVR-A could become a target to set-up new prevention strategies. The possibility to have in our hands a reliable marker, which could be easily measured in the future (through non-invasive strategies) to identify people at risk to develop insulin resistance, would represent a big novelty in the field of insulin resistance-associated disorders. To note, while it is possible to diagnosis systemic insulin resistance through direct (e.g. euglycemic clamp) or indirect (e.g. HOMA-IR) measures, clinicians do not still have reliable and easily accessible tools to evaluate brain insulin resistance. Considering the increasing burden of people suffering T2DM and AD in the next decades worldwide, the high gain deriving from the collected results will be to offer an instrument to manage such devastating disorders making feasible both healthy and economic benefits.
Furthermore, the proposed treatment could represent a breakthrough among the pharmacological interventions currently under evaluation in AD. This innovative paradigm shift in thinking, if confirmed by the studies of this proposal, is expected to lead to strategies that improve the quality of life of AD patients by modulating BVR-A activation.
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