Heterogeneity in the sn-1 carbon chain of platelet-activating factor glycerophospholipids determines pro- or anti-apoptotic signaling in primary neurons

Abstract

The platelet-activating factor (PAF) family of glycerophospholipids accumulates in damaged brain tissue following injury. Little is known about the role of individual isoforms in regulating neuronal survival. Here, we compared the neurotoxic and neuroprotective activities of 1-Ohexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C 16 -PAF) and 1-O-octadecyl-2-acetyl-sn-glycero-3-phosphocholine (C 18 -PAF) in cerebellar granule neurons. We find that both C 16 -PAF and C 18 -PAF cause PAF receptor-independent death but signal through different pathways. C 16 -PAF activates caspase-7, whereas C 18 -PAF triggers caspase-independent death in PAF receptor-deficient neurons. We further show that PAF receptor signaling is either pro-or anti-apoptotic, depending upon the identity of the sn-1 fatty acid of the PAF ligand. Activation of the PAF G-protein-coupled receptor (PAFR) by C 16 -PAF stimulation is anti-apoptotic and inhibits caspase-dependent death. Activation of PAFR by C 18 -PAF is pro-apoptotic. These results demonstrate the importance of the long-chain sn-1 fatty acid in regulating PAF-induced caspase-dependent apoptosis, caspase-independent neurodegeneration, and neuroprotection in the presence or absence of the PAF

Platelet-activating factors are associated with cognitive deficits in depressed coronary artery disease patients: a hypothesis-generating study

“…These results are also consistent with previous literature demonstrating that different PAF species have unique signaling effects both at the PAF receptor (a major conduit for PAF signaling) and independently of the PAF receptor [18]. For example, activation of the PAF receptor by PC( O- 16:0/2:0) has been shown to be anti-apoptotic, whereas activation by PC( O- 18:0/2:0) is pro-apoptotic.…”

“…Our results extend the previous literature, as several of the PAFs found to be associated with cognitive deficits in this study have established mechanistic relationships with neurodegenerative processes. For example, previous pre-clinical work has identified the PAFs PC( O- 18:0/2:0) and PC( O- 16:0/2:0) as important pathological species associated with pro-apoptotic effects in the central nervous system [18]. Furthermore, PC( O- 16:0/2:0) and its lyso -PAF precursor, PC( O- 16:0/0:0), were found to be elevated in the temporal cortex of patients with Alzheimer’s disease post-mortem [20], collectively implicating the PC( O- 16:0/2:0) pathway as a potential marker of neurodegeneration.…”

“…Platelet-activating factors (PAFs) are a diverse family of potent alkylacylglycerophosphocholine (lipid) second messengers. Emerging evidence suggests that PAF activation is a hallmark of pathological disruption to membrane-based lipid signaling cascades regulating inflammatory and apoptotic activity, with various PAFs demonstrating selective pro- and anti-inflammatory and neurodegenerative effects [13,18]. Accordingly, PAF activation has been associated with the presence of CAD and with inflammation, oxidative stress, and neurodegeneration; all contemporary mechanisms for depression in CAD [19].…”

Palmitate activation by fatty acid transport protein 4 as a model system for hepatocellular apoptosis and steatosis

“…It is not clear how FATP4 could mediate the synthesis of these lipids in this organelle perhaps involving inter-organelle trafficking. In addition, it is known that alkyl PC is a precursor of 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine or platelet-activating factor, and some of which are pro-apoptotic [53], and this lipid may contribute to some increase in apoptosis with FATP4 overexpression alone.…”

Platelet-activating Factor Contributes to Bacillus anthracis Lethal Toxin-associated Damage

“…Endothelial cell apoptosis has also been described in HUVEC cells by some but not all investigators (38,39,46). Interestingly, PAF was shown to promote apoptosis in a variety of cell types including neurons, corneal cells, and tumors (47)(48)(49)(50). Additional study will be needed to determine the role of PAF in LeTx-induced apoptosis.…”