Astrocytic Metabolic Reprogramming as a Therapeutic Target for Alzheimer’sDisease (HyperAstroMet)

Alzheimer's disease (AD) represents a growing public health challenge, with its prevalence steadily increasing profoundly affecting both patients and their families. Despite extensive research focusing on amyloid-beta and tau as central pathological hallmarks of AD, the crucial role of astrocytic metabolism in neurodegeneration has often been overlooked. The HyperAstroMet project introduces a novel approach by investigating astrocytic hypermetabolism as a pivotal driver of neuronal hyperexcitability, dysfunction, and cognitive decline in AD.

Astrocytes, integral to brain energy homeostasis, undergo significant metabolic reprogramming in the context of AD, marked by excessive glycolysis, altered glycogen storage, and disrupted insulin receptor signaling. These metabolic disturbances are thought to contribute to disease progression, yet their precise mechanisms remain poorly understood. This project aims to unravel the complex interplay between astrocytic metabolic dysfunction and neuronal degeneration in AD. Specifically, it seeks to identify new molecular targets for therapeutic intervention by elucidating how astrocytic hypermetabolism exacerbates neuronal dysfunction. Preliminary data from our lab suggest that targeting astrocytic glycolysis, particularly through GLUT1 ablation, can alleviate cognitive deficits and preserve neuronal integrity, potentially through compensatory upregulation of insulin receptor signaling.

However, the underlying mechanisms driving these improvements are still not fully elucidated. To address these knowledge gaps, HyperAstroMet employs cutting-edge methodologies, to monitor real-time astrocyte and neuronal activity and to dissect the therapeutic potential of targeting astrocytic metabolism. By focusing on astrocytic metabolic dysfunction, this research seeks to provide a transformative shift in the understanding of AD pathogenesis, moving beyond the amyloid-centric paradigm and opening new avenues for treatment and prevention.