LPS-induced neuroinflammation models: neurodegenerative processes

Lipopolysaccharide (LPS) serves as a potent trigger for the Toll-like receptor 4 (TLR4) signaling cascade within the central nervous system, primarily activating microglia and astrocytes. This activation initiates a robust neuroinflammatory response characterized by an exacerbated release of pro-inflammatory cytokines and the generation of reactive oxygen species. By effectively replicating key neurodegenerative hallmarks, including amyloid-β deposition, dopaminergic neuronal attrition, and synaptic impairment, LPS-induced experimental models provide a pivotal paradigm for elucidating the pathophysiology of Alzheimer’s and Parkinson’s diseases, as well as for evaluating the efficacy of emerging therapeutic interventions (1). Beyond the TLR4 pathway, LPS is recognized by specific transient receptor potential (TRP) channels, such as TRPA1, TRPV1, and TRPV4, which mediate rapid nociceptive responses and contribute to the modulation of neurogenic inflammation. Furthermore, intracellular recognition of LPS via inflammatory caspases (caspase-4/5 in humans, caspase-11 in mice) triggers the non-canonical inflammasome pathway, leading to Gasdermin D-mediated pyroptosis and the subsequent activation of the NLRP3 inflammasome, which further amplifies the neuroinflammatory cascade (1). In LPS-induced animal models, the resulting pathological phenotype is highly contingent upon the species, dosage, and administration frequency. This review aims to systematically compile the prevailing dosage regimens, animal species, and corresponding disease models employed to study LPS-triggered neuroinflammation. In a study using male C57BL/6J mice, a cognitive dysfunction model was established by administering LPS at a dose of 1 mg/kg, 30 minutes after a 7-day treatment (2). In a study involving male C57BL/6 J mice, a neuroinflammation model was established through continuous intraperitoneal injections of LPS at a dose of 250 μg/kg for 14 days, resulting in pathological changes in the hippocampus and impaired learning and memory abilities (3). In a study involving adult male C57BL/6J mice, a chronic neuroinflammation and cognitive decline model was established through a 28-day subcutaneous administration of either Porphyromonas gingivalis-LPS or Escherichia coli-LPS at a dose of 500 μg/kg. This chronic exposure induces AD-like pathology and neuroinflammation by activating TLR4 and TLR2 signaling pathways in microglial cells, even while the blood-brain barrier remains intact (4). LPS-induced neuroinflammation models are fundamental tools for investigating neurodegenerative pathologies, yet their outputs are significantly influenced by various experimental parameters. This review highlights that while intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) injections are the most prevalent routes, i.p. administration is often preferred for assessing peripheral-to-central inflammatory crosstalk without surgical interference. Peripherally administered LPS triggers neuroinflammation by increasing blood-brain barrier permeability through the disruption of tight and adherens junction proteins or via systemic inflammatory signals from circulating immune cells. Animal age remains a critical variable, as aged animals exhibit exacerbated inflammatory responses and greater sensitivity to LPS, particularly in the hippocampus, which often precedes cognitive and motor impairments. Dosage (ranging from 0.25 to 200 mg/kg) and exposure timing introduce substantial heterogeneity, with some paradigms revealing time-dependent intensification of effects and others suggesting compensatory or tolerance mechanisms. Refining these experimental variables is essential for achieving robust, reproducible results in the characterization of inflammation-mediated neurodegeneration (5).

References

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4. Eid, F., Boushehri, M., Boucher, C., Rajkanth, N., Sa, A.F., Alhoutan, T., Vavetsi, K., Dibart, S., Ma, Y. 2025. Chronic Lipopolysaccharide Exposure Causes AD-Like Pathology in Male Mice With Intact Blood–Brain Barrier. The FASEB Journal 39, 9. https://doi.org/10.1096/fj.202403117RR. 5. da Silva, A.A.F., Fiadeiro, M.B., Bernardino, L.I., Fonseca, C.S.P., Baltazar, G.M.F., Cristóvão, A.C.B. 2024. Lipopolysaccharide-induced animal models for neuroinflammation - An overview. Journal of Neuroimmunology 15, 387:578273. https://doi.org/10.1016/j.jneuroim.2023.578273.