ArticlebioRxiv : the preprint server for biology2025
Evidence for cPLA2 activation in Alzheimer's Disease Synaptic Pathology.
Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Synapses are essential for learning and memory, and their loss predicts cognitive decline in Alzheimer's disease (AD). Synaptic loss is associated with excitotoxicity, neuroinflammation, amyloid-β, and tau pathology, but the molecular mechanisms remain unclear. There is an urgent need to identify new targets to modify the disease and slow synaptic loss and cognitive decline. This study examines if calcium-dependent phospholipase A2 (cPLA2) is implicated in AD synaptic loss. cPLA2 catalyzes membrane phospholipids to release arachidonic acid, which can be metabolized into inflammatory eicosanoids. Methods: cPLA2 levels were examined in synaptosomes isolated from the postmortem frontal cortex of individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD dementia from the Religious Orders Study (ROS). Eicosanoids in synaptosomes were analyzed using lipidomics. Immunofluorescent staining investigated cPLA2 interactions with synaptic markers. Human iPSCs-derived neurons were used to study cPLA2 overactivation after exposure to amyloid-β 42 oligomers (Aβ42O), its relationships with synaptic markers, and the effects of cPLA2 inhibitors. Results: We observed elevated cPLA2 (cPLA2α and cPLA2β) in AD synaptosomes and positive correlations with postsynaptic density protein 95 (PSD-95) and cognitive dysfunction. Eicosanoids were increased in AD synaptosomes and correlated with cPLA2, indicating cPLA2 activity at synapses/synaptosomes. Phosphorylated cPLA2α (p-cPLA2α) colocalized with PSD-95 in synaptosomes, and with postsynaptic Ca Conclusions: cPLA2 overactivation at synapses, dendrites, and excitatory neuronal somas is associated with synaptic loss, neuritic plaques and neurodegeneration, potentially contributing to cognitive decline in AD. Future research needs to explore the role of cPLA2 as a disease-modifying target for AD.
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