Pseudolaric Acid A and Pseudolaric Acid B Exert Dual Neuroprotection: Inhibiting Aβ-Induced PC12 Apoptosis and Neuroinflammation with Therapeutic Potential in Alzheimer’s Disease Mice

Abstract Objective: Alzheimer’s disease (AD) is a neurodegenerative disorder with no effective prevention strategy. This study explored the neuroprotective effects of pseudolaric acid A (PAA) and pseudolaric acid B (PAB) against Aβ25–35-induced PC12 cell apoptosis and their anti-inflammatory roles in macrophages/microglia. We also assessed PAB’s therapeutic potential in an AD mouse model. Method: To dissect the potential antiapoptotic and anti-inflammatory mechanisms of PAA and PAB, we established distinct in vitro models, including the Aβ25–35-induced PC12 apoptosis model and LPS-stimulated BV2 microglia/RAW264.7 macrophage inflammatory models. The effects of PAA and PAB on cell viability, apoptosis, inflammation, migration, NO release, ROS levels, miRNA-155 expression, and related protein expression were investigated in vitro. Subsequently, the AlCl3-induced AD mouse model was established, and the effects of PAB on spatial learning/memory abilities and hippocampal neurons were evaluated by the Morris water maze and HE staining. Result: Our in vitro results showed that PAA and PAB could inhibit the apoptosis of PC12 cells induced by Aβ25–35 by regulating the expression of IRS-1, p-Akt, and p-GSK-3β. In parallel, PAA and PAB could alleviate the inflammatory response of macrophages and microglia induced by LPS by regulating the expression of P-Iκ-Bα/Iκ-Bα, TNF-α, and TGF-β1. Furthermore, behavioral tests showed that PAB had a certain therapeutic effect on AD model mice, as evidenced by improved spatial learning and memory. Conclusion: Our in vitro findings indicate that PAA and PAB exert neuroprotective effects via two distinct mechanisms: inhibiting apoptosis through PI3K/Akt signaling and attenuating neuroinflammation through NF-κB/miR-155 modulation. In vivo, PAB improved cognitive function in AD model mice. Although further validation is required to confirm these mechanisms in vivo, these results support the therapeutic potential of PAA and PAB for AD.