Ricerc@Sapienza

Growing evidence highlighted that metabolic defects are a risk factor for the development of Alzheimer disease (AD). This striking association spurs the necessity to further explore the molecular mechanisms underlying brain metabolic regulation that fuels neuronal activity. Within this picture, alterations of brain insulin signaling, known as brain insulin resistance, were reported to foster the development of AD. Indeed, insulin signaling regulates the maintenance of synaptic plasticity, the cell stress response and the neuronal metabolism, which are processes central to cognitive and learning functions. It comes that development of brain insulin resistance impairs all these functions. Recovering brain insulin signaling activation is challenging because once brain insulin resistance developed administration of insulin (through the intranasal route) promotes only wake effects. Indeed, from a molecular point of view insulin resistance is characterized by the uncoupling between IR and IRS1, meaning that even if insulin binds to IR, the following IRS1 activation does not occur. To overcome this limitation, published studies suggest the use glucagon-like peptide 1 (GLP1)-mimetics. GLP1 pathway, shares the same molecular targets with the insulin signaling cascade, named the MAPK and the PI3K/Akt pathway, downstream form GLP1 receptor (GLP-1R). Hence, through the activation of GLP1 pathway it is possible to bypass the uncoupling between IR and IRS1. Since GLP1 is rapidly degraded by DPP4 enzyme, maintaining elevated levels of GLP1 in the brain represents a promising strategy. Our project will evaluate age-associated changes of DPP4 levels and activity along with alterations of brain insulin signaling and AD neuropathology in the brain of 3xTg-AD mice and WT. Furthermore, we will test the neuroprotective effects of intranasal sitagliptin (a well-known DPP4 inhibitor) administration in improving brain insulin signaling and AD neuropathology in 3xTg-AD mice.