NF-κB as a driver of neurotoxic astrocytes in Alzheimers disease

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PROJECT SUMMARY Astrocytes participate in several intrinsic functions in brain areas deeply affected by Alzheimer's disease (AD). Under physiological conditions, astrocytes modulate synaptic plasticity, provide nutrients and support for neuronal survival, and contribute to higher cognitive functions and immune responses. However, astrocytes lose their protective phenotype and become increasingly detrimental during neurodegenerative disorders. Given the close association of astrocytes to brain disorders, it is surprising how little is known about the pathological function of these cells in disease processes. In AD, astrocytes become increasingly prominent as the disease progresses. We previously showed that these cells are highly plastic and can produce signals that either exacerbate or mitigate AD pathogenesis, indicating that modulating astrocytic function could have therapeutic value. Although mechanistic studies are yet to be developed, transcriptomic and proteomic approaches have provided clues to the molecular processes that potentially drive the pathogenic properties of astrocytes, with the nuclear factor-κB (NF-κB) being a promising candidate. NF-κB is a key transcriptional regulator of inflammation that has been linked to many chronic immune-related diseases. Our proposal seeks to use newly engineered genetic tools to investigate the hypothesis that chronic activation of astrocytic NF-κB impairs brain function and drives AD pathogenesis. These studies will provide definitive evidence of the pivotal role played by NF-κB in astrocytic function and its potential as a target to treat AD. !