PLENARY SESSION: Role of Compartmentalized Inflammation in Health and CNS Diseases*

Astrocytes undergo dramatic changes in response to stroke, particularly including localized changes in astrocytic immune responses. We will discuss changes in astrocyte immune responses after both cortical and white matter stroke that appear to be conserved in other types of CNS injury, suggesting a core astrocytic transcriptomic immune response that may be broadly targetable. 

Glial activation and neuroinflammation play critical but complex roles in the pathogenesis of Alzheimer Disease (AD). The circaidan clocks regulate glial cell gene expression, activation state, and function, and may be a novel therapeutic target for AD.

Targeting ADAM10 in developing new therapeutic approaches in patients with Alzheimer’s Disease (AD) has been a trending topic recently given its remarkable role in cleaving Amyloid beta (AB) to soluble particles, thereby preventing AB plaques accumulation. However, it has remained unclear if ADAM10 pathway predominantly runs intraneurons or in extraneuronal spaces like astrocytes and synapses. We aimed to compare the level of ADAM10 intra and extra neurons to better guide the pharmacological interventions. In AD patients, ADAM10 was significantly higher (two to three times more) in extraneuronal space regardless of the presence of Tau tangles, TDP43 or AB plaques. Level of ADAM10 was directly correlated with AB 1-42 levels across all groups with various pathological findings (Tau+/-, AB+/-, TDP43+/-). Elevated levels of ADAM10 in extracellular fluid may reflect increased AB accumulation in the brain. Our findings also suggest the potential development of new targeted medications to enhance ADAM10 stability.

In multiple sclerosis, the peripheral immune system targets and damages myelin, oligodendrocytes and axons. Within the central nervous system compartment, microglia, astrocytes and oligodendrocyte precursor cells react to demyelination and axonal damage, and their reactive responses influence the ability to repair and replace lost myelin. The mechanisms that underly these reactive responses offer novel therapeutic targets for progressive multiple sclerosis biology. 

Optic pathway glioma (OPG) is a low-grade astrocytoma seen in 15-20% of children with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Up to 50% of children with NF1-OPG develop retinal ganglion cell (RGC) death and visual impairment, which occurs three times more frequently in girls. Leveraging a validated murine model of Nf1-OPG, we previously demonstrated that estrogen mediates RGC death by inducing glial production of IL-1β, an inflammatory cytokine toxic to Nf1-mutant RGCs. Herein, we present evidence that estrogen-induced IL-1β expression in Nf1-OPG is dependent on NFκB activation. In a proof-of-concept study, we demonstrated that inhibition of NFκB using an FDA-approved pharmacological agent reduces IL-1β production and protects against retinal pathology in female Nf1-OPG mice. These results suggest that estrogen activates the NFκB signaling cascade to induce IL-1β expression in Nf1-OPG, and NFκB inhibition may be a novel therapeutic strategy to attenuate vision loss in children with NF1-OPG.

We will discuss microglia and their potential as a neurotherapy in pediatric neuroimmunological diseases