Alzheimer’s disease (AD) is an aging-associated neurodegenerative disorder in which dysregulated neuroinflammation drives disease progression. Although long noncoding RNAs (lncRNAs) are increasingly implicated in AD, their mechanistic roles remain poorly defined. Here, we identified a novel lncRNA termed LIMASI (LncRNA Inflammation and Mucous associated, Antisense to ICAM1), that is linked with AD-associated neuroinflammation. LIMASI expression is significantly elevated in postmortem AD brain tissues and in a 3xTg-AD mouse model by qPCR and RNA fluorescence in situ hybridization, and its upregulation is correlated with increased β-amyloid plaque burden, tau hyperphosphorylation, and heightened neuroinflammatory activation. Cell type-specific analyses demonstrated inflammation-inducible LIMASI expression in astrocytes and microglia. In an in vitro model of AD-associated neuroinflammation, viral mimetic poly(I:C) challenge of amyloid precursor protein (APP)-overexpressing neuroblastoma cells elicited coordinated induction of LIMASI and key inflammatory mediators. Mechanistically, we observed elevated levels of inflammatory microRNAs (miR-155-5p and miR-150-5p) in AD brain tissues, and computational modeling predicted energetically favorable interactions between these miRNAs and LIMASI. These findings support a competing endogenous RNA (ceRNA) model in which LIMASI sequesters pro-inflammatory miRNAs to modulate neuroinflammatory gene networks. Together, our data identify LIMASI as a putative ceRNA strongly associated with AD-related neuroinflammation and suggest that targeting LIMASI may represent a novel strategy to attenuate neuroinflammatory signaling and potentially slow AD-associated neurodegeneration.
Devadoss et al. (Fri,) studied this question.