Insulin Signaling in Alzheimer’s Disease Brain and Models Thereof

Brain insulin signaling acts as a key regulator for gene expression and cellular metabolism, both of which sustain neuronal activity and synaptic plasticity mechanisms. Alterations in this pathway, known as brain insulin resistance, are associated with a higher risk of developing age-related cognitive decline and neurodegeneration. Studies from our group have uncovered the role of the enzyme biliverdin reductase A (BVR-A) in this process. BVR-A, beyond its activity in the degradation pathway of heme, is a novel regulator of insulin signaling. BVR-A is a direct target of the insulin receptor, similar to insulin receptor substrate-1 (IRS-1). The insulin receptor phosphorylates BVR-A on specific Tyr residues, activating it to function as a Ser/Thr/Tyr kinase. In addition, downstream from IRS-1, BVR-A works as a scaffold protein, promoting the translocation of GLUT4-containing vesicles to the plasma membrane (to increase glucose uptake in response to insulin), the AKT-mediated inhibition of GSK3β (which promotes cell survival), and the AMPK-mediated inhibition of MTOR (which is involved in autophagy). Our group's groundbreaking findings have revealed that oxidative stress-induced impairment of BVR-A is a key event driving brain insulin resistance development in Alzheimer's disease (AD). Conversely, rescuing BVR-A activity reduces oxidative stress levels and improves brain insulin signaling, both of which contribute to improved cognitive function in animal models of neurodegeneration. Overall, our data suggest that BVR-A represents a molecular link between oxidative stress and insulin signaling, and studies to further investigate its role in the development of neurodegenerative disorders are ongoing in our lab.

Thursday 23/03/2023 Aula A CU010 13:00 Prof. Eugenio Barone Department of Biochemical Sciences -Sapienza University

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