N⁵-((perfluorophenyl)amino)glutamine regulates BACE1, tau phosphorylation, synaptic function, and neuroinflammation in Alzheimer’s disease models

SUMMARY: Alzheimer’s disease (AD) is the most common type of dementia. Its incidence is rising rapidly as the global population ages, leading to a significant social and economic burden. AD involves complex pathologies, including amyloid plaque accumulation, synaptic dysfunction, and neuroinflammation. This study explores the therapeutic potential of N⁵-((perfluorophenyl)amino)glutamine (RA-PF), a derivative of γ-glutamyl-N’-(2-hydroxyphenyl)hydrazide (Ramalin), a compound with antioxidant and anti-inflammatory properties. Administration of RA-PF to 5xFAD mice decreases BACE1, reduces Aβ plaque deposition, inhibits microglial activation, restores synaptic transmission, and improves mitochondrial motility, leading to the recovery of cognitive function. Additionally, RA-PF treatment in 3xTg-AD mice alleviates anxiety-like behaviors, tau phosphorylation via inactivating GSK-3β, and BACE1 expression. Further transcriptomic analysis reveals RA-PF treatment in AD mice models recovers phagosome, inflammation, NOD-like receptor, presynaptic membrane, and postsynaptic membrane related signaling pathways. These findings suggest that RA-PF effectively targets multiple aspects of AD pathology, offering a novel multi-target approach for AD treatment.