Evidence for cPLA2 activation in Alzheimer's Disease Synaptic Pathology

Ma, Q.-L.; Ebright, B.; Li, B.; Li, J.; Galvan, J.; Sanchez, A.; Renteln, M.; Dikeman, D.; Wang, S.; Kerman, B. E.; Seidler, P. M.; Gutierrez-Grebenkova, B.; Hjelm, B. E.; Hawes, D.; Hiniker, A. E.; Hurth, K. M.; Bennett, D. A.; Louie, S. G.; Chui, H. C.; Limon, A.; Arvanitakis, Z.; Yassine, H. N.

doi:10.1101/2025.03.27.645605

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bioRxiv · 10.1101/2025.03.27.645605

Evidence for cPLA2 activation in Alzheimer's Disease Synaptic Pathology

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Abstract

BackgroundSynapses are essential for learning and memory, and their loss predicts cognitive decline in Alzheimers disease (AD). Synaptic loss is associated with excitotoxicity, neuroinflammation, amyloid-{beta}, 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. MethodscPLA2 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-{beta} 42 oligomers (A{beta}42O), its relationships with synaptic markers, and the effects of cPLA2 inhibitors. ResultsWe observed elevated cPLA2 (cPLA2 and cPLA2{beta}) 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 cPLA2 (p-cPLA2) colocalized with PSD-95 in synaptosomes, and with postsynaptic Ca2+/calmodulin-dependent protein kinase II (CaMKII) and dendritic microtubule-associated protein 2 (MAP2) in NCI and AD brains, where their levels were reduced in AD. P-cPLA2 colocalizes with MAP2 at the neuronal soma associated with neuritic plaques and neurodegeneration in AD. A{beta}42O activates cPLA2 in human iPSCs-derived neurons, leading to p-cPLA2 relocation from the cytosol to synaptic and dendritic sites to colocalize with CaMKII and MAP2, resulting in their reduction. P-cPLA2 also colocalized with PSD-95 in A{beta}42O-exposed neurons, accompanied with increased PSD-95 intensity at soma membrane. These processes were reversed by the cPLA2 inhibitor ASB14780. ConclusionscPLA2 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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Ma, Q.-L., Ebright, B., Li, B., Li, J., Galvan, J., Sanchez, A., Renteln, M., Dikeman, D., Wang, S., Kerman, B. E., Seidler, P. M., Gutierrez-Grebenkova, B., Hjelm, B. E., Hawes, D., Hiniker, A. E., Hurth, K. M., Bennett, D. A., Louie, S. G., Chui, H. C., Limon, A., Arvanitakis, Z., Yassine, H. N.. 2025-04-01. Evidence for cPLA2 activation in Alzheimer's Disease Synaptic Pathology. https://doi.org/10.1101/2025.03.27.645605

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