Synaptic deposition of lysophospholipids at stresses - risk of the regional lipotoxicity for brain diseases

Synapses are ‘double-edged swords’, being appropriate for the quick transmission of impulses in one hand, but vulnerable to the oxidative stress in another hand. When the presynaptic terminals convey neurotransmission by altering structure of lipid molecules in response to physiological stimuli, membrane remodeling occurs rapidly at dendrites to make synaptic vesicles and release neurotransmitters. However, excessive stimuli due to stresses such as ischemia, trauma, irradiation, etc., cause changes of lipidomes at the presynaptic membranes to generate various lysophospholipids by overactivating phospholipase A 2 (PLA 2 ) and autotaxin. Lysophosphatidylcholine (LysoPC) is generated from the membraneous phosphatidylcholine (PC) via PLA 2 , while lysophosphatidic acid (LysoPA) is generated from LysoPC via autotaxin. LysoPC at the synaptic area enhances the membrane excitability, and LysoPA interferes with the cytoskeleton, both facilitating neuronal injuries. Here, the author focused on the ultrastructural visualization of lysophospholipids to elucidate detrimental effects of stress-induced lysophospholipids which were generated at the synaptic area. Lipidomics can detect LysoPC and LysoPA involved in the body fluids, however, cannot detect LysoPC accumulated in the restricted brain area. This is due to an insufficient spatial resolution of standard lipidomic/mass spectrometry approaches, and/or a technical limitation specific to LysoPC extraction/detection in the brain tissue. Since tannic acid interacts with the choline head-group of PC or LysoPC, and tannic acid-choline aggregates are postfixed by osmium tetroxide, it was utilized to visualize them by electron microscopy. Using tannic acid, PC is ultrastructurally observed as distinct double membrane structures, whereas LysoPC is visualized as extramembraneous, multilamellar bodies. In the monkey brain after ischemia, multilamellar bodies were clearly seen in the vicinity of synaptic vesicle membranes of hippocampal neurons. This review highlights the regional toxicity of lysophopholipids due to the transition from physiological lipid remodeling to pathological PLA 2 overactivation.