Long non-coding RNAs in glial cells: key drivers of neuroinflammation in cognitive disorders.

Neurodegenerative diseases (NDs) are characterized by the progressive deterioration of cognitive and motor functions. In this context, glial cell-mediated neuroinflammation is recognized as a key driver of disease progression. Long non-coding RNAs (lncRNAs) have emerged as key epigenetic regulators that modulate gene expression and inflammatory signaling pathways in this context. Due to their high cell-type specificity and dynamic regulation, lncRNAs are promising diagnostic biomarkers and therapeutic targets for NDs. The balance between the neuroprotective and proinflammatory functions of glial cells plays a crucial role in ND progression. LncRNAs act as multifunctional modulators of glial activity, influencing neuroinflammatory responses, astrocyte and microglia dysfunction, and the clearance of toxic protein aggregates. Several lncRNAs, including RMST, MALAT1, and NEAT1, regulate inflammatory pathways through various molecular mechanisms. For example, they act as competing endogenous RNAs that absorb microRNAs. These regulatory networks influence key signaling cascades involved in neuroinflammation, including Toll-like receptor (TLR)-mediated pathways, the NF-κB signaling axis, and NLRP3 inflammasome activation. In this review, we summarize and categorize glial lncRNAs according to their molecular interactions and functional roles in disorders related to cognitive decline. By integrating current evidence, we highlight the contribution of lncRNA-mediated regulatory networks to neuroinflammatory processes and discuss their potential as biomarkers and therapeutic targets. Our findings suggest that glial lncRNAs are crucial regulators of neuroinflammation in cognitive disorders. Their ability to modulate pathways such as the NLRP3 inflammasome makes them promising diagnostic biomarkers and therapeutic targets. Targeting these molecular networks provides new opportunities to halt neurodegeneration and improve clinical outcomes.