Plasmalogens are a class of molecules known as a phospholipid. Technically speaking, plasmalogens are among the most common class of glycerophospholipid that are found in biological membranes. In human and animal biology, plasmalogens are commonly found in cell membranes in the nervous, immune, and cardiovascular systems.

In the Russian paper Prospects for the diagnosis and treatment of plasmalogen deficiency, S.I. Polyakova et. al. cite five main functions of plasmalogens in human biology: they regulate the fluidity and integrity of cell membranes and organelles; they store and release polyunsaturated fatty acids and control cholesterol levels; they maintain membrane cohesion and continuity; they participate in signal transduction through the formation of liposomes and vesicles; and they have antioxidant activity.

In a paper out of McMaster University in Canada, Bozelli et. al. note that “lately, plasmalogens have begun to attract more attention due to their association with several degenerative and metabolic disorders as well as aging.” Plasmalogen replacement therapy, i.e. therapeutic supplementation with plasmalogens, has begun to generate interest for multiple disease states.

Plasmalogen Deficiency

Plasmalogen deficiency can be the result of both decreased synthesis and increased degradation, which has been found in respiratory disorders, inflammatory conditions and Alzheimer’s disease. It can also result from the upregulation of phospholipase A2, which is an enzyme used in the break-down of phospholipids.

Plasmalogen deficiency is observed in multiple disease states, including Parkinson’s disease, schizophrenia, peroxisome fusion diseases (Zellweger spectrum disorders, Refsum disease, rhizomelic chondrodysplasia punctata), as well as Niemann-Pick disease type C, Down syndrome, Barth syndrome, autism spectrum disorders, and neuronal ceroid lipofuscinosis. The content of plasmalogens is also reduced in other pathological conditions, including Alzheimer’s disease, myocardial ischemia, and spinal cord injury.

In Alzheimer’s disease a loss of up to 60% of plasmalogens from cell membranes in the brain has been observed. D.B. Goodenowe et al. showed Alzheimer’s patients had decreased levels of circulating plasmalogens in serum, as well as postmortem in gray and white matter of the brain. The significance and degree of this decrease are correlated with the severity of dementia. In addition, a linear regression model predicted that plasmalogen levels in serum decrease several years before the onset of clinical symptoms. The loss of plasmalogens in the brain in Alzheimer’s disease may also occur due to oxidative damage, which leads to the degradation of plasmalogens by free radicals.

Deficiency of plasmalogens is also associated with bronchopulmonary pathology (chronic obstructive pulmonary disease (COPD)). Plasmalogens make up about 3% of lung surfactant, a unique phospholipid and protein composition whose specific function is to reduce surface tension at the pulmonary air-liquid interface and protect the lungs from the aggressive effects of reactive oxygen species. Plasmalogens play an important role in the endothelial cells’ reaction to inflammation. Dysfunction of this reaction is an important pathophysiologic mechanism for the development of various diseases, in particular bronchopulmonary pathology.

Plasmalogens in cell and organ structure

Plasmalogens play an important role in bone, eye and brain development.

Plasmalogens are also crucial for Schwann cell development and differentiation. Schwann cells are a type of glial cell of the peripheral nervous system that help form the myelin sheath around the nerve fibers and play crucial roles in the maintenance and regeneration of the motor and sensory neurons of the peripheral nervous system. Defects in Schwann cell development impair radial sorting, myelination, and myelin structure. T.F. da Silva et al. [2014] demonstrated the necessity for plasmalogens in the proper and timely differentiation of Schwann cells and thereby for the process of myelination.

In the early postnatal period, plasmalogens are important for axon-glia interaction and myelination.

Sources of Plasmalogens

Marine shellfish, a popular foodstuff in many countries, is rich in plasmenyl-phospholipids including plasmalogens. Currently, a diet rich in seafood is the most acceptable source of plasmalogens for humans. At the same time, bioactive supplements developed using the internal organs of sea creatures are recommended for use only as sources of polyunsaturated fats, without taking into account the presence of lipids with an alkyl group in them, narrowing the known spectrum of their biological action. Therefore, there is a lack of preparations with highly purified plasmalogens on the market.

Therapeutic use of Plasmalogens

In Investigation of the physiological and biochemical effectiveness of plasmalogens and astaxanthin in microencapsulated form, study authors V.A. Sarkisyan et al. found a significant increase in the grip strength in animals treated with an emulsion with encapsulated plasmalogens and astaxanthin, which indicates an increase in strength and endurance. In the Morris water maze test, animals of the same group showed the best learning ability, indicating an improvement in cognitive functions. A more than 3-fold decrease in blood corticosterone levels in the animals treated with plasmalogens and astaxanthin, regardless of the form of administration, compared to control groups, indicates an adaptogenic effect and requires further study. The consumption of the emulsions led to a significant improvement in lipid metabolism: a significant decrease in serum cholesterol by 20% was shown, against the background of a significant reduction in LDL cholesterol by 25%.

In the paper Prospects for the use of natural alkyl glycerols in the target therapy of bronchial asthma with obesity, Novgorodtseva et al. note that changes in plasmalogen levels are observed in both obesity and bronchial asthma. Given the common mechanisms of metabolic signaling disorders in bronchial asthma and obesity (which they detail in the literature review), the authors note that “the therapeutic strategy of treatment of patients with bronchial asthma combined with obesity can be aimed at modification of intracellular signaling pathways responsible for inflammatory cell activation.” They note that, while the use of phospholipids has shown therapeutic effects with no side effects, research on plasmalogens is lacking. They are confident that the use of alkyl-glycerol esters from sea creatures “will make it possible to modify intracellular signaling pathways responsible for inflammatory cell activation in obesity-associated [bronchial asthma].”

Plasmalogens in Dementia

In the article Promising Strategies to Reduce the SARS-CoV-2 Amyloid Deposition in the Brain and Prevent COVID-19-Exacerbated Dementia and Alzheimer’s Disease, Navolokin et al. highlight novel discoveries in the treatment of neurological symptoms caused by COVID-19-mediated amyloid accumulation in the brain. They also examine strategies to stimulate the clearance of amyloids from the brain, looking specifically at plasmalogens, among other interventions.

The authors note that neurological symptoms are reported in up to 30% of COVID-19 cases (including memory loss, cognitive impairment, fatigue, brain fog, and insomnia) and may appear long after the infection (long COVID). “However, despite the lack of a clear understanding of whether COVID-19 causes pathological amyloid accumulation in the brain or whether it aggravates already ongoing neurodegenerative processes, the indisputable fact is that the COVID-19 infection is accompanied by amyloid aggravation in the brain associated with the neurological disorders, including symptoms of [Alzheimer’s] and dementia.”

Plasmalogens status, according to the authors, can be used as a biomarker for the functionality of peroxisomes, as well as being a therapeutic target. Circulating levels of plasmalogens may indicate how far Alzheimer’s disease has progressed.

Given the growing evidence of the improvement of cognitive deficits in those with neurodegenerative diseases, the authors speculate that plasmalogens can reduce the incidence of cognitive impairment in subjects with mild forgetfulness, Alzheimer’s and Parkinson’s disease by increasing plasma ethanolamine plasmalogen (PlsEtn) levels. It has also been shown that phosphatidylserine plasmalogen species improve cognitive disorders after cerebrovascular injury.

Studies have found marine plasmalogens improve memory deficit by the activation of neurogenesis in aged mice. Neuroinflammation caused by amyloid deposition is associated with the suppressed expression of brain-derived neurotrophic factor (BDNF) and a reduction in neurogenesis. These changes lead to neural death and neurite degeneration. Yet the administration of plasmalogens reduces depositions of amyloid beta in the brain and tau hyperphosphorylation, which leads to a reduction in neuroinflammation.

Chicken plasmalogens also enhance memory by the same mechanism: reduction in neuroinflammation. “However, marine PlsEtn enhances memory function better than chicken-derived plasmalogens, probably because marine PlsEtn is richer in DHA than the chicken derivative.”

Studies have shown that brain cortex levels of plasma ethanolamine plasmalogen which contain DHA correlate with cognitive abilities of rats with Alzheimer’s. In vitro studies have demonstrated that PlsEtn which contains DHA strongly suppresses neuronal inflammation, apoptosis, γ-secretase activity, and amyloid beta accumulation.

Studies have also demonstrated that the administration of plasmalogens systemically for 1 week was able to reduce microglia inflammation caused by amyloid beta aggregation. Longer treatment over the course of 15 months decreased both the expression of inflammatory markers and the protein kinase C-δ (PKCδ) involved in cell death.

References

Polyakova S.I., Zasurtsev G.V., Parshina P.V., Kobrinskiy B.A. Prospects for the diagnosis and treatment of plasmalogen deficiency. Ros Vestn Perinatol i Pediatr 2021; 66:(4): 16–24 (in Russ). DOI: 10.21508/1027–4065–2021–66–4–16–24

Sarkisyan V.A., Sidorova Yu.S., Petrov N.A., Frolova Yu.V., Kochetkova A.A. Investigation of the physiological and biochemical effectiveness of plasmalogens and astaxanthin in microencapsulated form. Voprosy pitaniia [Problems of Nutrition]. 2021; 90 (5): 38–48. DOI: https://doi.org/10.33029/0042-8833-2021-90-5-38-48 (in Russian)

Novgorodtseva T.P., Kytikova O.Y., Gvozdenko T.A., Antonyuk M.V. Prospects for the use of natural alkyl glycerols in the target therapy of bronchial asthma with obesity. Сибирский научный медицинский журнал [Siberian Scientific Medical Journal]. 2018;38(6):103-110. https://doi.org/10.15372/SSMJ20180615

Promising Strategies to Reduce the SARS-CoV-2 Amyloid Deposition in the Brain and Prevent COVID-19-Exacerbated Dementia and Alzheimer’s Disease

Navolokin, N.; Adushkina, V.; Zlatogorskaya, D.; Telnova, V.; Evsiukova, A.; Vodovozova, E.; Eroshova, A.; Dosadina, E.; Diduk, S.; Semyachkina-Glushkovskaya, O. Promising Strategies to Reduce the SARS-CoV-2 Amyloid Deposition in the Brain and Prevent COVID-19- Exacerbated Dementia and Alzheimer’s Disease. Pharmaceuticals 2024,17,788. https://doi.org/ 10.3390/ph17060788