Dysregulated Astrocyte p38, Brain Inflammation, and Alzheimer's Pathology

Test the hypothesis that astrocyte p38 activation in response to inflammatory stress stimulates production of IL-33, which then propagates proinflammatory responses and leads to neuronal damage.

Astrocytes, the most abundant glial cell type in the brain, become abnormally activated early in Alzheimer’s disease (AD) and can lead to detrimental brain inflammation and nerve cell damage. The p38 MAPK drives inflammation in microglia but its role in astrocytes is understudied. Our project will use novel mouse models and well-characterized human biospecimens to define the potential linkage between astrocyte p38, neuroinflammation, and AD neuropathologic change, thus providing new insight into mechanisms by which abnormal astrocyte activation in AD contributes to disease progression.

Innovation is in the use of both novel mouse models and well-characterized human biospecimens to explore p38 signaling in astrocytes (rather than microglia or neurons) and clarify how this pathway links neuroinflammatory changes and synaptic/neuronal pathology. Our studies will also shed light on the potential damaging versus beneficial effects of IL-33, an understudied cytokine. Understanding the role of IL-33 in modulating brain immune dysregulation could have implications for both AD and macular degeneration, as IL-33 has been implicated as a potential therapeutic target in both disorders.

Small molecule p38 inhibitors are currently in AD clinical trials. Our study will clarify the importance of astrocyte changes within this therapeutic class, helping to inform optimal dosing strategies to maximize likelihood of their eventual clinical success. Our data with human brain may suggest novel fluid biomarkers for astrocyte activation, neuroinflammation, and neurodegeneration, potentially providing future biomarker-based strategies for selection of clinical trial participants as well as monitoring response to therapeutic interventions, current areas of high interest in the field.