Journal Article

AS1842856 Reduces β‐Amyloid Burden via Inhibiting PLA2G4A‐Mediated Lysosomal Dysfunction in APP/PS1 Mice

Fan, Yong‐Gang, Qiu, Yi‐Min, Wu, Zheng, Jia, Rong‐Jun, He, Da‐Long, Wu, Ting‐Yao

2026

Overview

Aims Both cytosolic phospholipase A2 (PLA2G4A)‐induced lysosomal membrane disruption and glycogen synthase kinase‐3α/β (GSK3α/β)‐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 GSK3α/β. 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, β‐amyloid (Aβ) load, and lysosomal integrity, with its mechanism of action further explored in N2a‐sw cells. Results AS treatment reduced GSK3α/β 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 Aβ. Consequently, AS administration alleviated Aβ burden and improved cognitive function in APP/PS1 mice. Moreover, AS was found to inhibit NF‐κB‐mediated PLA2G4A expression. Knockdown experiments further revealed that reduced GSK3β—but not GSK3α—reproduced the suppressive effect on PLA2G4A. Conclusion Our study identified the GSK3β/NF‐κB/PLA2G4A signaling axis as a novel therapeutic target in AD, and AS could inhibit this axis to mitigate Aβ pathology by promoting lysosomal degradation of Aβ. AS1842856 reduces intracellular levels of GSK3α/β by binding to them and promoting their exocytosis. This reduction leads to diminished GSK3β‐mediated activation of NF‐κB, resulting in decreased transcription of PLA2G4A and reduced lysosomal damage. Ultimately, this enhances lysosomal degradation of Aβ, lowering Aβ load in APP/PS1 mice.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: Acidification / Alzheimer Disease - drug therapy / Alzheimer Disease - genetics / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer's disease / Amyloid beta-Peptides - metabolism / Amyloid beta-Protein Precursor - genetics / Animals / Antibodies / AS1842856 / Biotechnology industry / Brain / Cell Line, Tumor / Cognitive ability / cytosolic phospholipase A2 / Disease Models, Animal / Enzymes / Ethics / Glycogen / Glycogen synthase kinase 3 / Glycogen Synthase Kinase 3 beta - metabolism / Group IV Phospholipases A2 - antagonists & inhibitors / Group IV Phospholipases A2 - metabolism / Homeostasis / Kinases / Laboratory animals / lysosome / Lysosomes / Lysosomes - drug effects / Lysosomes - metabolism / Lysosomes - pathology / Male / Medical laboratories / Mice / Mice, Transgenic / Neurodegenerative diseases / Original / Phospholipase A2 / Presenilin 1 / Presenilin-1 - genetics / Proteins / Software / Therapeutic targets / Transgenic animals / β-Amyloid