Evidence for cPLA2 activation in Alzheimer’s disease synaptic pathology

Synaptic integrity is essential for learning and memory, and its loss is a strong predictor of cognitive decline in Alzheimer’s disease (AD). Although synaptic degeneration has been linked to excitotoxicity, neuroinflammation, and amyloid-β (Aβ) and tau pathology, the underlying mechanisms remain unclear. We investigated whether calcium-dependent cytosolic phospholipase A2 (cPLA2), an enzyme that releases arachidonic acid from membrane phospholipids, contributes to synaptic loss in AD. cPLA2 isoforms were quantified in synaptosomes isolated from postmortem frontal cortex of individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD dementia from the Religious Orders Study, and in human iPSC-derived neurons exposed to Aβ42 oligomers. Both cPLA2α and cPLA2β were elevated in AD synaptosomes and correlated with postsynaptic protein PSD-95, but not presynaptic markers. cPLA2β levels were strongly associated with cognitive dysfunction, particularly in males, and synaptosomal eicosanoids were increased and correlated with cPLA2. In iPSC-derived neurons, Aβ42 oligomers activated cPLA2α, promoted its phosphorylation and translocation to postsynaptic compartments, and induced PSD-95 loss—effects prevented by the selective cPLA2 inhibitor BRI-50460. These findings implicate cPLA2 overactivation in excitatory synaptic pathology and cognitive decline in AD, highlighting cPLA2 as a potential disease-modifying therapeutic target.