Lipopolysaccharide-induced Neuroimmune Alteration and Memory Decline in Aging Mice: The Role of Augmented Cellular Senescence.

Alzheimer’s disease (AD) remains a complex neurodegenerative disorder with multifactorial etiologies, often eluding effective modeling in preclinical studies. However, whether neuroinflammation, exacerbated by accelerated cellular senescence, is central to AD pathology induced by lipopolysaccharide, an endotoxemia agent, remains unknown. This study investigated a combination of lipopolysaccharide (LPS)-induced AD-like neuroinflammation with doxycycline-induced conditioned cellular senescence in mice. Following a 21-day doxycycline (DOXY)-induced cellular senescence in mice, neuroinflammation was induced by LPS from days 15–21. AD-related cognitive decline was investigated through spatial and non-spatial memory tests, oxidative stress, molybdoenzymes, acetylcholinesterase activity, inflammation, amyloid-beta levels, hypoxia-inducible factor (HIF-α) and brain-derived neurotrophic factors (BDNF) in brain regions affected by AD pathology, such as the hippocampus and prefrontal cortex (PFC). Behavioral assessments revealed that both LPS and DOXY independently impaired spatial and non-spatial working memory, locomotor activity, social interaction, and recognition memory, with their interactive treatment exacerbating these deficits significantly. Biochemical analyses revealed synergistic increases in pro-inflammatory cytokines (IL-1β, TNF-α, but not IL-4), oxidative stress markers (malondialdehyde, nitrite), astrocyte activation (GFAP), and amyloid-beta levels, with decreases in antioxidant defenses (GSH, GST, SOD, catalase) in the hippocampus and PFC. The DOXY + LPS group showed higher serum corticosterone levels, increased sulphite-oxidase in the PFC, and increased xanthine-oxidase and acetylcholinesterase in both regions, indicating an amplified stress response and cholinergic dysfunction. Conversely, DOXY + LPS interaction lowered hippocampal-targeted BDNF and HIF-α levels. These findings validate the role of cellular senescence in enhancing LPS-induced neuroinflammation, mimicking complex AD features, and provide a model for testing disease mechanisms and therapeutics.