The neuroinflammatory nexus: glial dysfunction in the pathogenesis and therapeutic targeting of neurodegenerative and neurodevelopmental disorders

Abstract

Chronic neuroinflammation is increasingly recognized as a fundamental driver of both neurodegenerative and neurodevelopmental disorders, linking immune dysregulation, glial dysfunction, and disease progression. In neurodegenerative protein misfolding disorders (NPMDs), including Alzheimer's disease, Parkinson's disease, and prion diseases, sustained microglial and astrocytic activation exacerbates protein aggregation, synaptic dysfunction, and neuronal loss, accelerating cognitive decline. Similarly, in neurodevelopment, aberrant inflammatory signaling during critical windows of brain maturation impairs synaptic formation, alters neurotransmitter systems, and predisposes individuals to long-term cognitive and behavioral deficits. Despite distinct manifestations, both disease categories share a pathological feature: a maladaptive neuroimmune response disrupting neural homeostasis. While neuroinflammation is widely implicated in these disorders, defining its molecular mechanisms, identifying therapeutic targets, and understanding environmental contributions remain critical research needs. This dissertation begins to address these gaps by investigating neuroinflammation as both a therapeutic target in NPMDs and a mechanistic link between environmental exposures and neurodevelopmental disruption. The first investigation evaluates SB_NI_112, a novel brain-penetrant RNA-based therapeutic designed to selectively inhibit NF-κB and NLRP3 inflammasome pathways, key regulators of glial activation and chronic neuroinflammation. Pharmacokinetic and biodistribution studies in small- and large-animal models were first conducted to assess SB_NI_112's CNS penetration and safety. These studies confirmed robust brain bioavailability (~30%) and a favorable safety profile, supporting its viability for therapeutic application. Following these findings, SB_NI_112 was tested in a murine prion disease model, where treatment significantly reduced microglial and astrocytic activation in disease-relevant brain regions, preserved hippocampal neurons, and mitigated neurodegeneration. These neuroprotective effects corresponded with improved cognitive performance in novel object recognition tasks, indicating functional preservation despite ongoing prion pathology. Notably, SB_NI_112 treatment extended survival, reinforcing inflammasome inhibition as a viable therapeutic strategy for NPMDs. These findings provide strong proof-of-concept for targeting neuroinflammatory pathways to slow disease progression and preserve cognitive function in neurodegenerative protein misfolding disorders. The second investigation examines the role of environmental neurotoxicants in triggering neuroinflammation and impairing neurodevelopment. Using a juvenile mouse model, this study demonstrates that chronic low-dose manganese (Mn) exposure (50 mg/kg via drinking water) first alters gut microbiome composition, depleting the relative abundance of beneficial Lactobacillaceae, and increasing the relative abundance of pro-inflammatory Erysipelotrichaceae, contributing to gut-brain axis dysfunction. These microbial shifts coincide with significant gliosis in the enteric nervous system, suggesting early neuroimmune activation at the gut interface. This inflammatory response extends to the brain, where widespread microglial and astrocytic activation is observed alongside disruptions in neurotransmitter production and metabolism, including altered dopamine and serotonin homeostasis. Functionally, these neuroimmune and neurochemical disruptions correspond with changes in behavior, indicating impaired neural processing. The presence of inflammatory lesions in the intestinal lining further implicates gut inflammation as a mediator of Mn-induced neurodevelopmental deficits. These findings highlight the systemic impact of Mn exposure, reinforcing the link between environmental toxins, neuroinflammation, and behavioral dysregulation. Together, these studies further support the growing body of evidence that neuroinflammation is a primary driver of neurological disease rather than a secondary consequence, reinforcing the need for targeted neuroimmune interventions. By examining shared inflammatory features across NPMDs and environmentally induced neurodevelopmental disruptions, this work provides additional insight into how glial dysfunction contributes to neurological pathology. These findings support the continued development of neuroimmune-modulating therapeutics, emphasize early intervention, and highlight the importance of environmental risk mitigation. By bridging molecular, pharmacological, and environmental perspectives, this dissertation contributes to the broader understanding of neuroinflammation in disease progression, challenging traditional distinctions between neurological disorders and providing a foundation for future studies. The implications extend beyond basic science, offering translational potential for clinical intervention, public health strategies, and regulatory policies to reduce the burden of neuroinflammatory disease.