LPS-Induced Neuroinflammation in Neurodegenerative Diseases: A Double-Edged Sword?

Lipopolysaccharide (LPS), a glycolipid endotoxin derived from Gram-negative bacteria, activates Toll-like receptor 4 (TLR4) signaling in microglia and astrocytes, initiating neuroimmune cascades characterized by pro-inflammatory cytokine release, oxidative stress, and glial reactivity. Chronic or high-dose LPS exposure promotes sustained neuroinflammation, blood-brain barrier disruption, impaired amyloid-β (Aβ) clearance in Alzheimer's disease (AD), and exacerbated α-synuclein pathology in Parkinson's disease (PD). In contrast, low-dose or intermittent exposure may promote adaptive neuroimmune responses characterized by regulated glial signaling and enhanced neuronal resilience. Emerging evidence suggests that these divergent outcomes are shaped by the biological context of LPS exposure, including dose, duration, route of administration, and host inflammatory status. The gut-brain axis further modulates these effects by linking peripheral inflammatory signals and microbial metabolites to central nervous system responses. Despite growing mechanistic insight, important knowledge gaps remain, particularly regarding the translational relevance of region-specific glial responses in humans. Improved understanding of context-dependent LPS signaling may help explain inconsistencies across experimental studies, refine neuroinflammation models, and support the development of therapeutic strategies targeting TLR4 signaling, autophagy, and gut-brain interactions. Collectively, current evidence suggests that LPS-induced neuroinflammation exists along a dynamic continuum, with transient immune activation potentially supporting adaptive neuroimmune responses, whereas chronic or dysregulated exposure promotes sustained neuroinflammation and progressive neurodegenerative changes.