PFK-158

Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid-β (Aβ) deposition, synaptic dysfunction, and progressive cognitive decline. Emerging evidence suggests that peripheral inflammation, particularly intestinal inflammation, can aggravate AD pathology through the gut-brain axis. As key mediators of intestinal inflammation and systemic immune activation, neutrophils have emerged as critical contributors to AD progression. In this study, we investigated how dextran sulfate sodium (DSS)-induced colitis influences Aβ pathology and synaptic integrity in 5 × FAD mice, focusing on the role of neutrophil glycolysis and neutrophil elastase (NE) activation. DSS-induced colitis significantly exacerbated AD-like pathology, as evidenced by pronounced body-weight loss, colon shortening, increased brain neutrophil infiltration, and elevated NE expression in the hippocampus, accompanied by enhanced Aβ plaque burden and reduced dendritic spine density. These findings indicate that DSS-triggered peripheral inflammation promotes central immune activation and accelerates Aβ pathology via metabolic reprogramming of neutrophils. Administration of the glycolytic inhibitor PFK-158 effectively suppressed NE expression and mitigated Aβ accumulation. Peripheral injection of PFK-158 attenuated neuroinflammation and partially restored dendritic structure, while intracerebroventricular infusion directly inhibited central neutrophil activation and improved hippocampal synaptic transmission, as reflected by enhanced field excitatory postsynaptic potentials (fEPSPs) and long-term potentiation (LTP). Collectively, these results demonstrate that DSS-induced colitis aggravates AD pathology by enhancing neutrophil glycolysis and NE release, linking peripheral metabolic inflammation to central neurodegeneration. Targeting neutrophil glycolytic activation with PFK-158 represents a promising therapeutic strategy to disrupt gut-brain inflammatory crosstalk and slow AD progression.