Original research Bifidobacterium breve LE4 Reduces Alzheimer's Disease Pathology and Confers Neuroprotection by Attenuating Neuroinflammation, Restoring Metabolism, and Preserving Gut Barrier

Emerging evidence implicates gut microbiota dysbiosis in Alzheimer's disease (AD) pathogenesis, suggesting probiotic interventions as a viable therapeutic strategy. This study systematically screened 18 Bifidobacterium strains, among which Bifidobacterium breve LE4 exhibited both potent antioxidant activity and lipopolysaccharide (LPS)-reducing capacity. Using APP/PS1 transgenic mice as an AD model, we comprehensively assessed the neuroprotective effects of B. breve LE4. The probiotic treatment significantly ameliorated cognitive impairments, particularly in spatial learning, and concurrently improving anxiety-like behaviors and locomotor activity. Notably, B. breve LE4 administration normalized metabolic disturbances, including body weight fluctuations, dyslipidemia, and glucose intolerance. At the molecular level, B. breve LE4 exerted potent anti-inflammatory effects by reducing systemic and hippocampal cytokine levels through modulation of the TLR4-NF-κB/NLRP3 signaling pathway. The probiotic intervention preserved intestinal barrier integrity, promoted beneficial gut microbiota remodeling, and enhanced short-chain fatty acids (SCFAs) production. These changes correlated with improved synaptic plasticity and reduced AD pathological markers, including Aβ deposition and tau hyperphosphorylation. Untargeted metabolomics revealed that B. breve LE4 administration significantly corrected AD-associated metabolic dysregulation, particularly affecting amino acid and lipid metabolism pathways. Our findings demonstrate that B. breve LE4 exerts multi-targeted protective effects against AD progression, providing compelling preclinical evidence for microbiota-based interventions in neurodegenerative diseases.