He_2026_CNS.Neurosci.Ther_32_e70910

AIMS: Both cytosolic phospholipase A2 (PLA2G4A)-induced lysosomal membrane disruption and glycogen synthase kinase-3alpha/beta (GSK3alpha/beta)-mediated lysosomal dysfunction have been implicated in neurodegeneration, with a potential regulatory relationship between these two pathways. We recently identified AS1842856 (AS) as a suppressor of GSK3alpha/beta. This study was therefore designed to investigate whether AS mitigates Alzheimer's disease (AD) progression by targeting PLA2G4A to restore lysosomal homeostasis. METHODS: The therapeutic potential of AS was investigated in APP/PS1 mice by analyzing cognitive function, beta-amyloid (Abeta) load, and lysosomal integrity, with its mechanism of action further explored in N2a-sw cells. RESULTS: AS treatment reduced GSK3alpha/beta expression in both APP/PS1 mice and N2a-sw cells. This suppression led to decreased PLA2G4A levels, restoration of lysosomal membrane integrity, and enhanced lysosomal degradation of Abeta. Consequently, AS administration alleviated Abeta burden and improved cognitive function in APP/PS1 mice. Moreover, AS was found to inhibit NF-kappaB-mediated PLA2G4A expression. Knockdown experiments further revealed that reduced GSK3beta-but not GSK3alpha-reproduced the suppressive effect on PLA2G4A. CONCLUSION: Our study identified the GSK3beta/NF-kappaB/PLA2G4A signaling axis as a novel therapeutic target in AD, and AS could inhibit this axis to mitigate Abeta pathology by promoting lysosomal degradation of Abeta.