The crucial role of brain insulin action in the regulation of systemic metabolism, energy balance, and glucose homeostasis, as well as in the modulation of cognitive function, is well established. However, the way in which impaired insulin signaling in the central nervous system, particularly in non-neuronal cells, contributes to the onset, manifestation, and progression of neurodegenerative disorders such as Alzheimer's disease (AD) is still not fully understood. Astrocytes are glial cells essential for brain homeostasis, as they regulate neuronal activity by providing metabolic and energetic support to neurons. According to our own preliminary data, we know that the specific disruption of insulin signaling in astrocytes reduces survival and exacerbates the onset of cognitive deficits in a murine model of AD. This early-onset cognitive decline is accompanied by a peripheral metabolic shift toward greater fatty acid utilization and reduced glucose uptake in the brain. These findings suggest that altered insulin signaling specifically in astrocytes—which we could term “astrocytic diabetes”—may represent a critical, yet still incompletely defined, event in the early stages of AD.
To further explore our hypothesis and unravel how this “astrocytic diabetes” may precede and significantly contribute to AD pathology, the overall objective of our project is to elucidate the mechanisms by which reduced insulin signaling in astrocytes impairs peripheral energy metabolism, decreases cerebral glucose uptake, reduces survival, and exacerbates the onset of AD-associated cognitive decline. To achieve this, three well-established and complementary experimental models of increasing complexity will be employed, ranging from C. elegans and mice to post-mortem human samples. In addition, we will use state-of-the-art techniques, such as spatial transcriptomics, brain calcium imaging through fiber photometry, and chemogenetics, to unravel the mechanistic basis of impaired insulin signaling during the development of neurodegenerative diseases.
In light of the dramatic global increase in metabolic disorders and the growing body of evidence demonstrating that energy metabolism and AD pathology are intimately linked, it is essential to decipher the role of altered astrocytic insulin signaling as a key event in the onset of AD. Our project could provide a better understanding of the mechanisms underlying the early stages of AD and will explore new avenues for future clinical research aimed at developing novel and effective therapies to delay the onset and progression of this disease.