What are Plasmalogens?

Plasmalogens are a type of phospholipid present in almost all tissues of human, and are most abundant in the brain. They are essential for their critical roles in memory, focus and cognitive functions. Plasmalogen levels in the body begins to increase from foetal stage and reach its peak by the 30s and start to decline thereafter. Research have indicated that this decline affects brain performance especially in plasmalogen-deficient seniors.

Structure of Plasmalogen

Plasmalogen is a type of phospholipid with glycerophospholipid as the parent compound.

Plasmalogen contains a fatty alcohol with a vinyl-ether bond (combination of an alkene and an ether) located at the sn-1 position and fatty acids, such as docosahexaenoic acid (DHA, omega-3) or arachidonic acid (AA, omega-6) located at the sn-2 position of the glycerol backbone. At the sn-3 position, the carbon links to an ethanolamine (ethanolamine plasmalogen) or a choline (choline plasmalogen) by means of a phosphate ester bond.

How are Plasmalogens Formed?

Plasmalogens are synthesized in peroxisomes (organelles). Peroxisomal function decreases with age and which in turn leads to decreased synthesis of plasmalogens.

Our brain is the organ that contains the highest amount of plasmalogens and they are a key component of neuronal membranes and myelin sheaths. Therefore, reduced plasmalogens in the brain have been shown to manifest in various neurodegenerative disorders including Alzheimer’s disease.

Plasmalogen-rich Food

Most plasmalogens in the body are biosynthesised (produced by our body). However, a small amount of plasmalogen can also be obtained from food sources such as scallop, chicken and cow breasts, shark liver oil and krill oil.

Scallop is a better source of plasmalogen for use by humans as its structure is closest to plasmalogens found in the human body thus far. In addition, plasmalogen extracted from scallop is enriched with two beneficial polyunsaturated fatty acids, DHA and EPA. Scallop-derived PLASMALOGEN serves the functions of plasmalogen as a whole, as well as the functions of DHA and EPA when these two polyunsaturated fatty acids are cleaved from the structure of plasmalogen.

Plasmalogen with DHA and EPA was found to have better and quicker effects on brain. They are essential fatty acids that can only be obtained from food as neither of them can be synthesised in our body. These two fatty acids are important for retinal, immune, cardiovascular, neuronal and cognitive functions.

Do you know?
The marine invertebrates have high ethanolamine plasmalogen (PlsEtn) contents. PlsEtn is present at high levels in the brain and they are believed to be involved in neuronal protection. PlsEtn species of marine foodstuffs are predominantly enriched with DHA and EPA; while PlsEtn species in land foodstuffs are enriched with eicosatetraenoic acid (ETA) (Yamashita Y et al., 2016). Hence, PlsEtn containing DHA and EPA from marine foodstuffs is potentially beneficial as a therapeutic dietary supplement to ameliorate and prevent neurodegenerative diseases, such as Alzheimer’s disease.

Distributions of Plasmalogens in Different Tissues

Distributions of Plasmalogens in Different Tissues

Plasmalogens constitute up to 20% of total phospholipid mass in human body. More than 50% of glycerophosphoethanolamine (GPEtn) fraction are found in brain, heart, neutrophils and eosinophils of human. In certain brain regions, plasmalogens may constitute up to nearly 90% of the GPEtn fraction. Furthermore, plasmalogens are also found abundantly in kidney and skeletal muscle. A high percentage of both ethanolamine plasmalogen (PlsEtn) and choline plasmalogen (PlsCho) are detected in heart and skeletal muscle. Liver is found to have the lowest amount of plasmalogens which can be related to their synthesis in liver and successive transport to other tissues by lipoproteins. (See table below)

In addition to tissues, plasmalogens are also important components of cell membrane (~15 to 20% of total phospholipids) and subcellular membranes including nucleus, mitochondrion, endoplasmic reticulum and post-Golgi network. Nonetheless, plasmalogens have not been detected in peroxisome membranes though their biosynthesis starts in peroxisomes. Plasmalogens are also found in specialized membranes, such as sarcolemma and myelin (part of nerve cell), as well as secreted membranes, such as synaptic vesicles, secretory granules and surfactant.

Distribution of plasmalogens in different tissues of human and other mammals.

Note: Total phospholipid content includes cardiolipin, GPEtn, PlsEtn, GPCho, PlsCho, GPIns, GPser and sphingomyelin.

This table was extracted from Braverman NE & Moser AB, 2012.

Abbreviation: PlsEtn: ethanolamine plasmalogen; PlsCho: choline plasmalogen; GPEtn: glycerophosphoethanolamine; GPCho: glycerophosphocholine; GPIns: glycerophosphoinositol; GPser: glycerophosphoserine; PL: phospholipid; LDL: low-density lipoprotein; HDL: high-density lipoprotein; VLDL: very low-density lipoprotein; CHO cells: Chinese Hamster Ovary cells.

 

Plasmalogen deficiency and other diseases:

In addition to Alzheimer’s, plasmalogen deficiency is also associated with various neurological, respiratory and other disorders.

Neurological disorders:

Many neurological disorders are associated with changes of plasmalogen levels, which could be due to a decrease of plasmalogen synthesis or an increase of their degradation.

Neurodegenerative diseases:

Brain is the tissue that contains the highest amount of plasmalogens and reduced plasmalogen levels in brain are associated with other neurodegenerative diseases such as Parkinson’s disease (Fabelo N et al., 2011), Neimann Pick type C (Schedin S et al., 1997), Down syndrome (Murphy E J et al., 2000) and experimental autoimmune encephalomyelitis (Singh I et al., 2004). Nonetheless, it remains elusive whether the reduced plasmalogen level is a leading cause or downstream effect of these pathologies.

Plasmalogen deficiency is also found to further exasperate brain injury in X-linked adrenoleukodystrophy (X-ALD) mouse model (Brites P et al., 2009). X-ALD is a genetic disorder that affects white matter of nervous system and adrenal cortex. Furthermore, decreased ethanolamine plasmalogen in white matter of brain in cerebral ALD patients has been shown to correlate with elevated reactive oxygen species (ROS) (Khan M et al., 2008).

Ischemic and hypoxic injury:

Ischemic injury is the most typical clinical manifestation of cell injury by oxygen deprivation due to inadequate blood supply. A remarkable plasmalogen loss of neural membranes has been observed in ischemic injury. This is probably due to an increased catabolism of plasmalogens by plasmalogen-selective PLA2. In rabbit, 10-fold increase of plasmalogen-selective PLA2 has been detected in myocardium (muscular wall of heart) during ischemic injury (Hazen SL et al.,1991). This stimulation of plasmalogen-selective PLA2 was also observed during hypoxic injury in rabbit (Portilla D et al., 1994). Hypoxia is a condition of oxygen deprivation due to reduced amounts or saturation of hemoglobin.

Spinal cord injury:

Plasmalogens account for approximately 1/3 of total glycerophospholipids in spinal cord with majority of PlsEtn is detected in myelin sheath. Degradation of PlsEtn in both grey and white matters is similar throughout and after spinal cord compression (pressure exerted on spinal cord) (Demediuk P et al., 1985). During the first minute of compression, approximately 10% of plasmalogens are lost. This plasmalogen loss is then increased to 18% at 30 minutes after compression injury. This loss of plasmalogens can be explained by activation of plasmalogen-selective PLA2 in spinal cord injury which may also cause alteration in membrane fluidity and permeability, leading to increased influx of calcium ions, impaired mitochondrial function and formation of ROS. All of these conditions probably contribute to neurodegeneration in spinal cord injury. Among the symptoms of spinal cord injury are inability to move arms and legs, urinary and fecal incontinence, unconsciousness and others.

Peroxisomal disorders:

Plasmalogen deficiency is featured in Zellweger syndrome, which is an autosomal recessive disease. During development, PlsEtn are increasingly enriched in adrenic and oleic acids (polyunsaturated fatty acids) in normal myelin. However, in the brains of Zellweger syndrome patients, PlsEtn is deficient of both adrenic and oleic acids, which implying abnormalities in this disease. In brief, plasmalogens are deficient quantitatively and qualitatively with alteration of polyunsaturated fatty acids in Zellweger syndrome. The plasmalogen deficiency is suggested to be caused by insufficient mRNA for enzymes of ether lipid synthesis (Martinez M et al., 2000).

Fetal alcohol syndrome:

Fetal alcohol syndrome (FAS) may be due to persistent ethanol consumption by mother during pregnancy. Newborn with FAS have defective intelligence, motor function and hyperactivity. The mechanism of this brain damage remains elusive. Nonetheless, ethanol consumption is hypothesized to affect the accumulation of DHA in brain development in which this fatty acid is required for the synthesis of plasmalogens in peroxisomes. Another finding also revealed that developing and adult brains have lower DHA and plasmalogen levels in neural membranes with ethanol exposure (Wing D R et al., 1982; Hofteig JH et al., 1985). The low DHA levels in fetal’s brain triggered by ethanol can be restored by increasing dietary DHA intake by mother.

Malnutrition:

Plasmalogen levels were found to be lower in neonatal undernourished brain tissue. The reduced plasmalogen levels correlate to decreasing number of synapses per unit area of undernourished brain (Shoemaker WJ & Bloom FE, 1977). Improvement of nutrition restores phospholipid content and reverses morphological changes in undernourished brain (Reddy TS et al., 1982).

Respiratory disorders:

Low plasmalogen levels in body have been associated to respiratory diseases such as bronchopulmonary dysplasia (BPD) and chronic obstructive pulmonary disease (COPD). BPD, a chronic lung disorder of infants and children, is a dominant cause of morbidity in prematurely born infants. Research has shown that premature infants with tracheal aspirates of low plasmalogen levels have an increased risk of developing BPD (Rudiger M et al., 2000). However, premature infants who were administered with surfactant preparations of high plasmalogen content resulted in better respiration (Rudiger M et al., 2005). Pulmonary surfactant is a surface-active phospholipoprotein formed by alveolar cells that reduces surface tension. Adding small amounts (2 mol%) of plasmalogens to surfactant-like phospholipid mixtures lowers the surface tension (Rudiger M et al., 1998). This proposes structural role of plasmalogen in surfactant. Considering newborns have relatively low plasmalogen levels, premature infants may have a higher risk of plasmalogen deficiency.

COPD is a progressive lung disease characterized by long-term poor airflow. Among the symptoms of this disease are breathing difficulty, wheezing, coughing with sputum production, chest tightness and others. Smoking is the major cause of COPD. Metabolic profiling of a large number of COPD patients revealed statistically significant correlation between smoking and plasmalogen deficiency. This was further supported by down-regulation of AGPS (responsible for a critical step in plasmalogen synthesis) transcript in lung tissues of smokers, implying a reduction in plasmalogen synthesis (Wang-Sattler R et al., 2008)

In consideration of lung is a direct target of reactive oxygen species (ROS), plasmalogen potentially protect against respiratory diseases via their antioxidant property. Plasmalogens in the lungs are enriched with arachidonic acid (AA, an omega-6 fatty acid involves in proinflammatory and immunosupportive), suggesting the role of plasmalogens in immune defenses. All these data propose that plasmalogens may play important roles in normal lung functions.

Other disorders:

Low-density lipoprotein (LDL) from patients with obese metabolic syndrome and type II diabetes are found to have decreased ethanolamine plasmalogen (PlsEtn) levels by 22% and 49% respectively and increased lipid peroxidation compared to controls (Colas R et al., 2011). In addition, PlsEtn levels are also detected to be lower by 20% in red blood cell membranes of hyperlipidemic (abnormally elevated levels of fat and fatty substances in blood) patients.