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 inthe 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.
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.
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.
Plasmalogens contain various kinds of unsaturated fatty acids and function differently depending on the kind of unsaturated fatty acids contained. Especially, plasmalogens, enriched in DHA*, are reported to be effective to brain function such as memory.
*DHA (Docosahexaenoic Acid): an omega-3 polyunsaturated fatty acid, an essential fatty acid that cannot be synthesized in the body and therefore must be obtained from food .
This slide outlines the activities of Pls, among which their antioxidative activity is the most-well known. Pls also play a role in ion transport, with cholesterol efflux capacity, and function as an eicosanoid precursor --- Eicosanoids are hormone-like substances, including the prostaglandins. Pls are known to function as a precursor to them or a platelet-activating factor. In short, they are crucial for life in all respects.
DHA - rich Food
Three capsules each were randomly drawn from commercially available plasmalogen supplements derived from scallops, chicken and ascidians, and then the fatty acids of ethanolamine plasmalogens (pl-PE), abundant in the brain, were measured by LC-MS/MS after lipid extraction. As shown in the chart, scallop-derived plasmalogens contain the highest amount of DHA. Three capsules each were randomly drawn from commercially available plasmalogen supplements derived from scallops, chicken and ascidians, and then the fatty acids of ethanolamine plasmalogens (pl-PE), abundant in the brain, were measured by LC-MS/MS after lipid extraction. As shown in the chart, scallop-derived plasmalogens
contain the highest amount of DHA.
Plasmalogens play an essential role neuron cells— providing unique structural attributes, facilitating signaling processes and protecting lipid membrane from oxidation reaction by free radicals. It has been reported that reduction of level of plasmalogen is correlated with cognition deficit, oxidative stress, and severity of diseases. Studies showed positive therapeutic outcomes with plasmalogen interventions in Alzheimer Disease (AD) patients. Furthermore, the severity of AD is improved when circulated level of DHA and plasmalogen were high. This suggests that plasmalogen may act asradical scavenger to protect cells from oxidative damages and reducing inflammatory in neurons.
HALL OF FAME FOR PIONEERS
Takehiko Fujino,MD,PhD, is an Emeritus Professor of Kyushu University. He graduated from Medical School of
Kyushu University, Japan, in 1964. He is strongly interested in the integrated medicine, especially in the
correlation between brain and other organs although his specialty was initially cardiology of internal medicine.
He advocated a new concept “Brain Fatigue”, from which many kinds of diseases might be induced, and
developed “BOOCS: Brain-Oriented Oneself-Care System”, a new method for removal of “Brain Fatigue” in
1991. It has been known that many kinds of disorders such as metabolic syndrome, depression and dementia
were improved and then the death rate of those patients decreased by “BOOCS” method. As one of those
researches, he has studied the correlation among “Brain Fatigue”, Alzheimer’s disease and plasmalogen.
Shiro Mawatari, MD, PhD, is a Director of Institute of Rheological functions of Food. He graduated from Medical
School of Kyushu University (Fukuoka, Japan) in 1964, and was engaged in biochemical research on erythrocyte membrane of dystrophy at School of Medicine at the University of Pennsylvania (Philadelphia, USA) and Columbia Neuroscience, Columbia University (New York, USA) for three years and a half. After returning to Japan, he worked as an associate professor at Kyushu Institute of Technology (Fukuoka, Japan) and a professor at Fukuoka Women’s University (Fukuoka, Japan). In recent 15 years, he has been dedicated to developing technology for measurement and extraction, and to developing functional food from raw materials with its
RESEARCH AND DEVELOPMENT
Takehiko Fujino, MD., PhD. Emeritus Professor, Kyushu University, the founder of BOOCS Medical Group, Japan had conducted the researches focusing on Plasmalogen replacement therapy, and reported positive outcomes from Scallop-extracted Plasmalogen which has been acknowledged world-wide HISTORY
Developed a method for measuring ether phospholipids in human serum by HPLC-ELSD method
Prove that plasmalogen activates Akt and ERK 1/2 via several orphan G protein-bound receptors
Ref: PLos ONE.2016,11:e0150846
Started open trials for people with moderate or sevior Alzheimer's disease and other dementia symptoms on January
Started large scale clinical trials for people with mild dementia(called as Alzheimer's disease) for scallop derived Plasmalogen on November Succeeded in extracting high-purity plasmalogen derived from sallops. Safety test completed.
Prove that Plasmalogen suppresses apoptosis through activation of Akt and ERK 1/2
Ref: Los ONE 2013,8:e83508
Started research on double shellfish to find for the better materials
Prove that erythrocyte Plasmalogen is reduced in patients with Alzheimer's disease
Ref: Dement Geriatr Cogn Disord Extra 2:298-303,2012
Patent pending 2010-001337
Prove that Plasmalogen administraion is effective in Alzheimer's disease by animal model
Remark:suppressess inflammation of brain nerve cells as well as amyloid-beta protein accumulation
Ref: Journal of Neuro inflammation 9:197-209,2012
Prove that oral administration of Plasmalogen increases erythrocyte plasmalogen
Ref: Lipids in Health and Disease 11:161-167,2012
Plasmalogen safety test completed
Confirmation of safety and improvement effects of Alzheimer's disease in human trial at medical institutions
Successful sophystification of the Plasmalogen detection,Simplification method
Ref:Analytical Biochemistry 370:54-59,2007
Discovered high purity plasmalogen extraction method from chicken meat Patent published 2006-23296 Patent pending 2007-16056
According to World Alzheimer Report 2015 from Alzheimer’s Disease International, 46.8 million people worldwide are living with dementia in 2015. This number will almost double every 20 years, reaching 74.7 million in 2030 and 131.5 million in 2050. It is well known there is still no drug capable of improving Alzheimer’s disease.
Ginsberg has first reported the close correlation between plasmalogen and Alzheimer’s disease, that is, plasmalogen was decreased in post mortem brain samples of Alzheimer's disease, compared with in other neurodegenerative diseases. Alzheimer ’ s disease is one of the most common form of dementia which accounts for 60 to 80% of all dementia cases. Stat istics from Alzheimer ’ s Disease International record approximate 44 million people worldwide living with Alzheimer ’ s disease or related dementia in 2016. It is the 6th leading cause of death in the United States, with one in three elderly dying of Alzheime r ’ s or other forms of dementia. Alzheimer ’ s may be among the costliest diseases for societies in Europe and the United States.
Goodenowe showed that circulating plasmalogen was decreased in serum from patients with Alzheimer's disease and the decrease of the plasmalogen correlated with the severity of dementia.
First, let me begin with the background of our study. These our studies made it possible for us to perform our clinical study. This slide outlines the progress of research on Pls, focusing on their association with Alzheimer’s disease. Research on Alzheimer’s disease was initially led by the United States; in 1995 and 1999, reduced levels of Pls in the brains of cadavers with Alzheimer’s disease
were noted, and, subsequently, in 2007, reductions in the serum levels of Pls in living patients with Alzheimer’s disease were reported. In Japan, we succeeded in developing a new, advanced detection method for Pls in 2007. We also developed a method for the extraction and production of high - purity Pls in 2009. The development of these methods facilitated the administration of Pls to animals and humans. Furthermore, we publis hed research papers in 2012 and 2013 reporting that Pls were effective in rats with Alzheimer’s disease, and in 2012 that the levels of Pls were reduced in the erythrocytes of patients with the disease. We conducted a randomized double - blind placebo - contro lled trial involving humans from Nov. 2014 to Apr. 2016
It is described that high - performance liquid chromatography can separate intact ethanolamine plasmalogens and choline plasmalogens as well as all other phospholipid classes by a single chromatog raphic run.
This slide shows the results of animal experiments using the plasmalogen which we extracted. Left panel shows the formations of dendrites in no application of plasmalogen. Right panel shows the those in application of plasmalogen, DIV6 means the sixth day from embryo, DIV 14 the fourteenth day embryo. These data shows direct application of plasmalogen enhances the formation of dendrites in primary hippocampal cultured neurons.
This figure explains plasmalogen enhance the neurogenesis the memory-related hippocampal cells of mice immunostaining data. As shown in the right panel, the Plasmalogen-diet mice showed more positive neurons in the dentate gyrus, compared with normal diet.
It is already known that Lipopolysaccharide (LPS), one of inflammatory agent, promotes amyloid-β accumulations, which induce Alzheimer’s disease. As shown at the LPS column, the cell is stained green, indicating that amyloidosis took place in the CA1 area of the hippocampus, after LPS administration. In contrast, after the simultaneous administration of LPS and Plasmalogen, as shown in the LPS + Plasmalogen column, the cell was not stained green. This indicates that amyloidosis did not occur when Plasmalogen were administered.
Plasmalogen promotes neurogenesis in senescence-accelerated mice and normal mice. This results in effective treatment of Alzheimer’s Disease. Plasmalogen inhibits neuroinflammation and amyloid β-protein accumulation in the brain. This results in effective prevention of Alzheimer’s Disease.
Knock down of plasmalogen synthesizing enzyme (GNPAT) by sh-RNA in the hippocampus reduced plasmalogen and impairs spatial memory. Dietary plasmalogen for 6 weeks increased hippocampal plasmalogen and enhanced memory task performance. Dietary plasmalogen activated Akt and ERK1/2, in the hippocampus, to phosphorylate CREB, then induced expression of brain-derived neurotrophic factor (BDNF), which is well known to enhance memory function by affecting neuronal plasticity and synapse/spine formation. plasmalogen are rich in membrane lipid rafts and dietary plasmalogen result in a localization of BDNF receptor, TrkB in the lipid raft. These findings suggest that plasmalogen may enhance the memory by activating BDNF- TrkB signaling in the hippocampus.
Here, I’ll talk about our Randomized Controlled Trial to examine the effects of Plasmalogen on patients with mild Alzheimer’s disease and Mild Cognitive Impairment.
Here is our study design. 328 patients, aged 60-85 years. They were randomized to receive either 1mg/day plasmalogens or placebo for 24 weeks. We assessed the safety to these patients by monthly clinic visit. Of 328 patients enrolled, 276 patients completed the 24- week follow-up.
Here is a breakdown of the study participants. Number of cases was 178 in Mild Cognitive Impairment, 98 in mild Alzheimer’s Disease.
Here we did the sub-analysis by sex and age in patients with mild Alzheimer’s Disease. Closed circle indicates Plasmalogen group, and open circle does placebo group, respectively. In female subjects, WMS-R, the marker of memory function, improved significantly in Plasmalogen group and there were significant differences between Plasmalogen and placebo groups as shown in the left panel. Right panel indicates the difference by age. In 77 or younger group, WMS-R significantly improved in Plasmalogen group and showed the significant differences between Plasmalogen and placebo groups.
This slide shows the changes in plasma and erythrocyte Plasmalogen levels following oral administration of Plasmalogen. Closed circle indicates Plasmalogen group. Open circle shows placebo group. In the placebo group, Plasmalogen level in plasma significantly decreased at endpoint, and the significant difference between Plasmalogen and placebo groups was observed.
As for moderate and severe Alzheimer’s disease, we conducted an open-label trial.
Here is a breakdown of the study participants. The number of cases was 57 in moderate Alzheimer’s disease and 18 in severe Alzheimer’s disease.
Here is our study design for an open-label trial. Participants received 1mg Pls orally per day for 3 months.
As shown in the left panel, 52.6 % of moderate AD improved significantly, while35.1% of those unchanged and 12.3% of those worsened. In severe AD, as shown in the right panel, 27.8% of those improved significantly. While 27.8% of those unchanged and 16.7% worsened.
Lastly, I will talk about discussion and conclusions. To our knowledge, this study is the first trial in the world that efficacy and change of blood plasmalogens by oral administration of plasmalogen were examined in patients with Alzheimer’s disease and mild cognitive impairment. These results suggest that 1) Oral administration of plasmalogen extracted from scallop improves cognitive functions in Alzheimer’s disease 2) Blood plasmalogen is useful for the assessment of cognitive functions, including the differentiation between Mild Cognitive Impairment and mild Alzheimer’s disease.
Plasmalogen Related Papers
- Orally administered plasmalogens alleviate negative mood states and enhance mentalconcentration: a randomized, double-blind, placebo-controlled trial.M.Fujino, et al.Front CellDev Biol 10:894734, 2022
- Plasmalogen-Mediated Activation of GPCR21 Regulates Cytolytic Activity of NK Cells againstthe Target Cells.S. Hossain, et al.J Immunol 209:310-325, 2022
- Plasmalogens, the vinyl ether-linkedglycerophospholipids, enhance learning and memory byregulating brain-derived neurotrophic factor. S.Hossain, et al.Front Cell Dev Biol10:828282, 2022
- Plasmalogenattenuates LPS-induced ICAM-1 expression in endothelial cell line.R.Kanda, et al.J Osaka Dent Univ 5: 179-185, 2021
- Therapeutic efficacy of plasmalogens for Alzheimer’s disease, Mild Cognitive Impairment andParkinson’s disease in conjunction with a new hypothesis for the etiology of Alzheimer’s disease.T. Fujino, etal. Peroxisome Biology. Lizard G (ed). Adv Exp Med Biol1299:195-212, 2020
- Biological Functions of Plasmalogens.S. Hossain, et al. Peroxisome Biology. Lizard G (ed). AdvExp Med Biol 1299:171-193,2020
- Improvement ofblood plasmalogens and clinicalsymptoms in Parkinson’sdisease by oraladministration of ether phospholipids: a preliminary report.S.Mawatari, et al. Parkinsons Dis2020:2671070, 2020
- Identification of plasmalogens in Bifidobacterium longum, but not in Bifidobacterium animalis.S.Mawatari, et al. J Sci Rep 10: 427, 2020
- Distinctfunctions of Acyl/Alkyldihydroxyacetonephosphate reductase in peroxisomes andendoplasmic reticulum.M.Honsho, et al.FrontCell Dev Biol 8:855, 2020
- Effects ofplasmalogen on patients withmoderate-to-severe Alzheimer’sdisease and bloodplasmalogen changes: a multi-center, open-label studyT. Fujino, et al. J Alzheimers DisParkinsonism9: 474, 2019
- PUFA-plasmalogens attenuate the LPS-induced nitric oxide production by inhibitingthe NF-kB,p38 MAPK and JNKpathways in microglial cells.M.Youssef,et al. Neuroscience 397: 18–30, 2019
- Plasmalogens inhibit endocytosis of toll-like receptor 4 to attenuate the inflammatory signalin microglialcells.F. Ali, et al. Mol Neurobiol 56: 3404-3419,2019
- Effects ofplasmalogen on patients with mild cognitive impairment: a randomized, placebo-controlled trialin Japan.T.Fujino,et al. J Alzheimers Dis Parkinsonism8: 419, 2018
- Plasma anderythrocyte membrane plasmalogens in patients withcoronary heart diseasesundergoing percutaneous intervention.T. Arita, et al. Cardiology and Angiology: An International
Journal 7: 1-11, 2018
- Scallop-derived plasmalogens attenuate the activation of PKCd associated with the braininflammation.S. Sejimo, et al.Biochem Biophys Res Commun503: 837-842, 2018
- Oral ingestion of plasmalogens can attenuate the LPS-induced memory loss and microglialactivation.MS. Hossain, et al.Biochem Biophys Res Commun496: 1033-1039, 2018
- Enzymatic measurement of etherphospholipids in human plasma after hydrolysis of plasmawith phospholipase A1.S.Mawatari,et al.Pract Lab Med 10:44-51, 2018
- Efficacy andblood plasmalogen changes by oral administration of plasmalogen in patients withmildAlzheimer’sdiseaseand mild cognitive impairment: a multicenter, randomized, double-blind, placebo-controlled trial.T. Fujino, et al.EBioMedicine 17: 199-205, 2017
- Plasma anderythrocyte membrane plasmalogen diminished in severe atheroscleroticpatients undergoingendovascular therapy.H.Noda,etal.Membrane42: 242-249, 2017
- Reduction ofether-type glycerophospholipids, plasmalogens, by NF-kBsignal leading tomicroglial activation.MS.Hossain,et al.J Neurosci 37:4074-4092, 2017
- Measurement of ether phospholipids in human plasma with HPLC-ELSD and LC/ESI-MS afterhydrolysis of plasma with phospholipase A1.S.Mawatari,et al. Lipids51:997-1006, 2016
- NeuronalorphanG-protein coupled receptor proteins mediateplasmalogens-induced activationof ERK and Aktsignaling.MS.Hossain,et al.PLoS One11:e0150846, 2016
- Bioactivelipids safeguard our brain from various challenges.TKatafuchiet al.Fukuoka IgakuZasshi106:293-301, 2015
- Plasmalogensrescue neuronal cell death through an activationof AKT and ERKsurvivalsignaling.MS.Hossain,et al.PLoS One 8:e83508, 2013
- Changes inphospholipid composition of erythrocyte membrane inAlzheimer’sdisease.S. Oma,et al. Dement Geriatr Cogn DisordExtra 2: 298-303, 2012
- Dietary plasmalogen increases erythrocyte membrane plasmalogen in rats.S.Mawatari, et al.Lipids Health Dis11:161, 2012
- Anti-inflammatory/anti-amyloidogenic effects of plasmalogens in lipopolysaccharide-inducedneuroinflammation in adult mice.M. Ifuku, et al. J Neuroinflammation 9: 197, 2012
- Effects of plasmalogens on systemic lipopolysaccharide-induced glial activationand β-amyloidaccumulation in adult mice.T. Katafuchi,et al.Ann N Y Acad Sci 1262:85-92,2012
- Simultaneouspreparation of purified plasmalogens and sphingomyelin in human erythrocyteswith phospholipase A1fromAspergillus orizae.S.Mawatari,et al.Biosci Biotechnol Biochem 73:2621-2625,2009
- Separation of intact plasmalogens and all other phospholipids by a single run of high-performance liquid chromatography.S.Mawatari,et al.Anal Biochem 370: 54-59, 2007