Relationship Between Astrocyte p38 MAPK, Neuroinflammation, and Alzheimer Pathology

A key mechanism that drives pathophysiology progression in many CNS disorders is dysregulated neuroinflammatory responses, especially inflammatory cytokine overproduction, from abnormally activated glia. Although most neuroinflammation research has focused on microglia as the primary immune cell of the brain, activated astrocytes also play important roles. The molecular mechanisms underlying astrocyte activation responses and the consequences for disease progression are complex and understudied. Our research is focused on a key cell signaling protein that contributes to neuroinflammatory responses in Alzheimer’s disease (AD): the p38alpha MAP kinase (p38). Activation of p38 occurs early in AD and can lead to chronic neuroinflammation that has neurodegenerative consequences, and small molecule p38 inhibitors are currently in AD clinical trials. Most research on p38 signaling has been done in microglia or neurons. This project will use novel mouse models with genetic knockout (KO) specifically in astrocytes and well-characterized human brain tissue to explore p38 signaling in astrocytes and clarify how this pathway links neuroinflammatory changes and AD-relevant synaptic/neuronal dysfunction. Our central hypothesis is that astrocyte p38 activation in response to inflammatory stress stimulates production of the inflammatory cytokine IL-33, which then propagates proinflammatory responses and leads to AD-relevant neuronal/synaptic damage.