Functions of Plasmalogens in the Brain

Plasmalogens are essential for the functioning of the brain. This includes regulating ion transport and cholesterol efflux, acting as a precursor for eicosanoid and platelet-activating factors, as well as supporting membrane fusion and antioxidant activity.

Antioxidation

Antioxidation is the most prominent role of plasmalogens. This anti-oxidative property is due to the presence of double bond (vinyl ether bond) in plasmalogen structure. In this way, plasmalogens (alkenylacyl glycerophospholipids) are preferentially oxidized when exposed to free radicals compared to diacyl glycerophospholipids. Plasmalogens protect brain cells which are subjected to oxidative stress by oxidizing themselves and preventing oxidation of polyunsaturated fatty acids and other susceptible membrane lipids. This suggests that plasmalogens play a role as sacrificial oxidants. Considering oxidative products of plasmalogens are not able to spread lipid peroxidation further, plasmalogens may cease lipid oxidation.

Research has shown that plasmalogen-deficient cells are more susceptible to cell death caused by free radical species compared to wild-type cells. In these wild-type cells, plasmalogens were specifically degraded in this process (Zoeller RA et al., 1988). Furthermore, experimental evidence also showed that plasmalogen-deficient cells are more susceptible to chemical hypoxia (which generates oxygen free radicals), superoxides and singlet oxygen and the presence of plasmalogens are required for recovery (Zoeller RA et al., 1999). This was further corroborated by another study that demonstrated elevated plasmalogen levels in cells reduce accumulation of reactive oxygen species and extend cell survival during hypoxia (Zoeller RA et al., 2002).

Structural Components of Neural Membranes

Neural membranes have substantial amounts of plasmalogens, which are a modulator of membrane dynamics. The integrity of neural membranes is important for the maintenance of normal cellular functions such as lipid packing, fluidity and interaction with receptors and ion channels of neural membrane.

Membrane Fusion

Ethanolamine plasmalogens (PlsEtn) are main endogenous lipid fraction that promotes membrane fusion between synaptic vesicles and neural membranes for the release of neurotransmitters. The amount and type of plasmalogen content determines optimal membrane fusion. In vitro study demonstrated that vesicles containing PlsEtn go through fusion six times faster than vesicles containing phosphatidylethanolamine (PtdEtn) (Lohner K et al., 1991). The rate of fusion is determined by types of fatty acid composition. PlsEtn containing 20:4 fatty acid fuses five times faster than the corresponding PlsEtn containing 18:1 fatty acid. In addition, small reductions in the vinyl ether and polyunsaturated fatty acid content in vesicles also affects membrane fusion events drastically. The membrane fusion behaviour of plasmalogens also relies on highly selective interaction between vesicles containing PlsEtn and a fusion protein. This interaction with a fusion protein together with high levels of plasmalogens in the synaptic plasma membrane proposes that plasmalogens may be taken part in vesicle formation during neurotransmitter release. In brief, plasmalogen deficiency would cause impaired vesicular fusion.

Precursor for Second Messengers

Considering plasmalogens are enriched with AA (arachidonic acid) and DHA, plasmalogens act as a rich reservoir for these biologically active lipid mediators which are released via phospholipase A2 (PLA2) hydrolysis. DHA and AA are precursors for potent metabolites involved in signal transduction.

AA is distributed evenly in the grey matter and white matter of central nervous system and also in various cell types. They are known to involve in regulation of gene expression, synaptic plasticity (changes) and neurodegenerative processes. AA is metabolized (changed into a form that can be used by body) to prostaglandins, leukotrienes, thromboxanes and lipoxins, which are collectively known as eicosanoids. Because of amphiphilic (possessing both water-loving and fat-loving properties) nature of eicosanoids, they can cross cell membranes and leave the cells in which they are synthesized to act on neighboring cells. This is noticed in neurons and may be implicated in communications between various types of neurons. DHA is found abundantly in neural membranes. DHA may be implicated in vesicle formation during neurotransmitter release.  In addition, DHA is metabolized to resolvins, docosatrienes and neuroprotectins which regulate inflammatory responses. Majority of AA and DHA are recycled.

In addition, intricate reaction triggered by action of plasmalogen-selective PLA2 on glycerophosphoethanolamine also releases platelet-activating factor (PAF). PAF is robust metabolites involved in platelet aggregation, allergic and inflammatory processes linked to ischemia (restriction in blood supply to tissues) and central nervous system trauma.

Cholesterol Efflux

  • Plasmalogen levels in cells are associated with high-density lipoprotein (HDL)-mediated cholesterol efflux. This is corroborated by observations that plasmalogen-deficient cells have reduced HDL-mediated cholesterol efflux and cells with restored plasmalogen levels have increased HDL-mediated cholesterol efflux (Mandel H et al., 1998). Cholesterol efflux is inversely associated with occurrence of arteriosclerotic cardiovascular disease, a heart disease caused by buildup of plaque made up of cholesterol, fat, calcium and other substances in blood. Normal aortas (main blood vessel of body) with increasing donor age and reduced plasmalogen levels were more remarkable in arteriosclerotic aortas (Buddecke and Andresen, 1959). Plasmalogens may play a vital role in pathogenesis (development manner of a disease) of arteriosclerosis with their antioxidant properties. Considering plasmalogens are more susceptible to oxidation compared to phosphatidylcholine and sphingomyelin, plasmalogens and HDL are probably favored targets of lipid peroxidation prior to oxidation of enormous polyunsaturated glycerophospholipids in low-density lipoprotein (LDL). The significance of LDL oxidation in arteriosclerosis is supported by observation of a greater oxidative susceptibility of LDL in patients with a greater severity of coronary (heart) arteriosclerosis. In addition, hyperlipidemic (high cholesterol and lipids in blood) patients have 20% lower PlsEtn level in red blood cell membrane lipids compared to normal healthy donors. In a nutshell, plasmalogens play a crucial part in cholesterol efflux.

Ion Transport

Plasmalogens play a significant role in calcium transport in which plasmalogens provide a particular lipid environment for the regulation of sodium-calcium exchanger. Sodium-calcium exchanger is mainly found in the cell membrane of excitatory cells such as neurons, and is a significant constituent of excitation-secretion machinery. In skeletal muscle, the relationship between PlsEtn and Ca2+-ATPase, a transport protein in cell membrane for calcium transport, has been described in sarcoplasmic reticulum (specialized type of smooth endoplasmic reticulum).

In addition, the levels of PlsEtn in red blood cells are associated with optimal activity of sodium-potassium pump (transmembrane protein). It has been proposed that the presumed preferential interaction between PlsEtn and membrane-embedded part of the pump will trigger a conformational change of the protein which subsequently hampering the contact of intracellular sodium ions to its binding site. Choline plasmalogen (PlsCho) in vesicles may also regulate function of gramicidin ion channel. Since DHA is involved in the synthesis of plasmalogens, both DHA and plasmalogens are suggested to be implicated in the maintenance of ion pumps in neural membranes.

Differentiation

Cell differentiation is the process where a cell changes from a less specialized type to a more specialized type during development, such as from neural stem cell to neural progenitor cell and from neural progenitor cell to neuron. Research has shown that the ratio for [3H]PlsEtn to [3H]PtdEtn incorporated by [3H]ethanolamine in progenitor cells was 1:3. This ratio was then increased to 2.3 at 2 days of differentiation of progenitor cells. This ratio was then further increased to 2.7 throughout 6 days of differentiation. Though this ratio was then decreased after 6 days of differentiation, [3H]ethanolamine incorporated into [3H]PlsEtn was 1.8 times higher compared to [3H]PtdEtn at 9 days of differentiation (Bichenkov and Ellingson, 1999). This observation suggests that plasmalogens play a crucial role during differentiation. This is further justified by another finding of elevated activities of plasmalogen-synthesizing enzymes in developing brain of rat (Wykle and Schremmer Lockmiller 1975).

Functions of plasmalogens