Swertisin improves Alzheimer's disease-like pathology in 5XFAD male mice through regulation in plasmin activity

초록

Abnormal accumulation of amyloid (3 (A(3), which may result from excessive production or impaired clearance, is one of the pathomechanisms of Alzheimer's disease (AD). Plasmin is one of the important proteases involved in the A(3 clearance system. In this study, we investigated whether swertisin can regulate plasmin activity and reduce A(3 pathology. First, we examined whether swertisin regulated plasmin activity, mature brain-derived neurotrophic factor (mBDNF) levels, and plasminogen activator inhibitor-1 (PAI-1) activity in vitro. Next, we assessed the effect of swertisin on memory impairments in an A(3-injected AD-like mouse model and in 5XFAD mice. To evaluate the involvement of plasmin in the effect of swertisin in the A(3-injected AD-like mouse model, we used 6-aminocaproic acid (6-AA), a plasmin inhibitor. Additionally, we measured plasmin activity and mBDNF levels in the hippocampus of A(3-injected AD-like mice and 5XFAD mice. Swertisin increased plasmin activity and mBDNF levels in hippocampal slices from both normal and 5XFAD mice. Moreover, swertisin ameliorated A(3-induced synaptic long-term potentiation (LTP) deficits in hippocampal slices. Swertisin also mitigated memory impairments induced by ventricular injection of A(3, and this effect was blocked by 6-AA. Furthermore, swertisin improved learning and memory in 5XFAD mice while reducing A(3 deposition and neuroinflammation. This study demonstrates that swertisin ameliorates AD-like pathology by regulating plasmin activity. Plasmin activated by swertisin may cleave A(3 aggregates and increase mBDNF levels, thereby protecting the brain from A(3 toxicity. Swertisin may represent an effective therapeutic strategy for AD patients.

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