STAT3 activation in astrocytes as a driver of neurovascular dysfunction in Alzheimer's disease and related dementias

项目总结

Project summary Alzheimer’s disease (AD) and related dementias (ADRD) are exacerbated by neurovascular dysfunction. Astrocytes are key contributors to neurovascular health and blood-brain barrier (BBB) function. In response to pathogenic stimuli, astrocytes adopt a “reactive” phenotype generally characterized by morphological changes. Recent research has shown that reactive astrocytes can adopt a diverse spectrum of molecular identities, but the interplay between these different subtypes of reactive astrocytes and the brain vasculature remains unclear. Indeed, some studies have shown that reactive astrocytes negatively influence BBB function, while others have shown that reactive astrocytes are vital to neurovascular repair after injury. Most of these studies have been performed in the context of stroke or physical trauma, and while there are some emerging studies at single-cell resolution on reactive astrocyte states in ADRDs, there is little to no information on how these different states may directly contribute to neurovascular dysfunction. Herein, we propose to investigate how STAT3 activation in astrocytes drives neurovascular dysfunction in ADRDs. In preliminary work, using thin sections from postmortem human brain tissue, we have shown that AD patients have significantly increased numbers of STAT3-activated astrocytes and inflamed blood vessels. In a human in vitro model of astrocytes cocultured with brain endothelial cells, we have shown that inflammatory stimuli activate STAT3 signaling in astrocytes, which leads to BBB disruption, and inhibition of STAT3 activation in astrocytes mitigates these outcomes. Further, using combinations of the human in vitro model, ex vivo mouse cortical slice cultures, and in vivo manipulations, we have shown that alpha 1-antichymotrypsin (ACT)—a STAT3-regulated serine protease inhibitor—contributes directly to neurovascular dysfunction. Moving forward, we will build on these promising results in the following manner. In Aim 1, we will expand our human tissue studies into larger ADRD cohorts and employ advanced imaging techniques to quantify three-dimensional spatial relationships between STAT3-activated astrocytes and sites of vascular damage. In Aim 2, we will inhibit STAT3 signaling in astrocytes within transgenic mouse models of ADRD and evaluate longitudinal alterations to neurovascular dysfunction; these assessments will include single-cell RNA sequencing to characterize molecular changes to endothelial cells along the entire vascular tree. In Aim 3, we will causally link astrocyte-derived ACT to neurovascular dysfunction in transgenic mouse models of ADRD, as well as characterize prospectively synergy between ACT and APOE, which have known connections in AD and dementia risk. Collectively, outcomes from this work will define the mechanistic roles of STAT3-activated astrocytes in neurovascular dysfunction associated with ADRD and identify potential avenues for targeting astrocytes as an ADRD treatment strategy.