Plasmalogens- exciting new evidence

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Re: Plasmalogens- exciting new evidence

Postby slacker » Sun Feb 18, 2018 8:27 am

slacker wrote:Do we know that tinkering with these other lipid markers results in higher plasmalogens? For example, pharmaceuticals designed to raise HDL were not successful in reducing coronary artery disease, despite the belief that those with higher HDL had greater protection. The devil is in the details...

julie g wrote:Of course, I can't answer your question without concurrently testing pre & post plasmalogen levels correlated with lipid changes. That said, I'm not sure that your analogy works. HDL-raising Pharma HAS previously failed to affect CAD risk/progression, but I'm suggesting using the old-fashioned method of diet and exercise to shift lipid markers that strongly correlate with high plasmalogen and inversely correlate with CAD.. Slide #73 tells a powerful story.


I agree that the plasmalogen angle deserves further investigation, and has the potential to yield huge benefits. It's hard for me to interpret slide #73 out of context. Maybe it would make more sense to me if I had heard the entire presentation as well as view the slides. I'm a mixed media audiovisual learner! My only point is that we don't yet know if the types of lifestyle changes we as a community are trying to make will result in higher plasmalogen levels, and less cognitive decline due to higher plasmalogens. A great and exciting theory still needs to be thoroughly investigated.

I look forward to Stavia's update on E4 and lipids. I continue to be awed and thankful for this group.
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Re: Plasmalogens- exciting new evidence

Postby Searcher » Sun Feb 18, 2018 8:51 am

Harrison wrote: can you get a bit more information about what "metabotypes" PLS1, PLS2, and PLS3 actually represent.


Harrison,

http://www.alzheimersanddementia.com/ar ... 52-5260(15)02354-7/pdf

PLS1 are those with the most plasmalogen, and PLS3 those with the least.

This abstract also reveals something about the risk of lower cognition. What explains that risk, in the sample of around 1000 persons studied?

The coefficient of correlation is

0.66 for plasmalogen level
-0.23 for E4

The square of the coefficient is an estimate of the proportion of risk explained by that factor.

So, (0.66^2 = 0.436 =) 44% of the risk of higher vs lower cognition is explained by plasmalogen level.

Similarly, 5% of the risk of higher vs lower cognition is explained by E4 level.

Plasmalogens start declining from the age of about 30.

It's enough for me to eat plasmalogens, in the form of shark liver oil. Plus more olive oil, oily fish and nuts for the precursors of plasmalogen.

Plasmalogen itself is a relatively simple molecule. I hope the synthetic versions will not be priced extortionately.

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Re: Plasmalogens- exciting new evidence

Postby Orangeblossom » Sun Feb 18, 2018 9:19 am

Sounds interesting. I'm not sure I understand the link with higher plasmalogen and HDL though. Would it be more able to cross the BBB due to it? And more reverse cholesterol transport, perhaps?

From the slides-

A low blood plasmalogen level is predictive of non-demented persons becoming demented in the near future;

A high blood plasmalogen level is protective against dementia: the incidence of dementia in persons with high blood plasmalogens is 80% lower than in persons with average or low blood plasmalogens;

So how can we check these levels? I note it is plasma levels as well, not levels in the brain...Would it relate to or be indicated by HDL / trigs ratio?

I was interested in the stuff to improve it and wonder if we would need to buy that stuff or could use something more natural perhaps.

I noticed that it seemed to help increase levels, eating it I mean, in rats anyway

https://www.researchgate.net/publicatio ... ma_in_Rats

"plasmalogen extracted from the bovine brain" Mmm sounds tasty :D Hopefully something a bit nicer could be found..

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Re: Plasmalogens- exciting new evidence

Postby Tincup » Sun Feb 18, 2018 9:29 am

Searcher wrote:"Plasmalogen precursors include omega-3 and omega-6 polyunsaturated fatty acids. At the sn-2 position, plasmalogens are enriched in polyunsaturated fatty acids, specifically docosahexaenoic, C22:6 ω−3 (DHA), or arachidonic acid, C20:4 ω−6 (AA)." So, good idea to eat more polyunsaturated fats, such as in oily fish and nuts.


Gundry wants us (as E4 patients) to consume at least 1g/day of DHA, but makes no mention of sn position. I didn't have time to get into this with him on a consult last Thursday. Dr. Jack Kruse is also a huge fan of DHA, and suggests making sure it is at the sn-2 position. He implies the only way to accomplish this is through consumption of seafood vs DHA supplements (which, I understand, tend to have the DHA spread fairly equally among sn-1, sn-2 & sn-3).
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Re: Plasmalogens- exciting new evidence

Postby Julie G » Sun Feb 18, 2018 10:03 am

It's hard for me to interpret slide #73 out of context. Maybe it would make more sense to me if I had heard the entire presentation as well as view the slides. I'm a mixed media audiovisual learner!

I hear you. Maybe we can make that happen... Simply stated, plamalogen levels are fairly difficult to test as very few labs in the country do them. The standard lipids on slide #73 show clear correlations that enable you to informally access where you stand.
My only point is that we don't yet know if the types of lifestyle changes we as a community are trying to make will result in higher plasmalogen levels, and less cognitive decline due to higher plasmalogens.

I can only speak for myself. The dietary and lifestyle changes I've adopted have led to my lipid ratios moving in the direction correlated with increased plasmalagen; HDL-98, TGs-50, HDL/LDL ratio- 1.24. George has spoken to the cognition angle.

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Re: Plasmalogens- exciting new evidence

Postby Julie G » Sun Feb 18, 2018 10:14 am

So how can we check these levels? I note it is plasma levels as well, not levels in the brain...Would it relate to or be indicated by HDL / trigs ratio?

Dayan (like Rasmussesn with APOE) is using plasma levels. The testing is not particularly difficult, but unfortunately not widely available. Once again, slide #73 answers your questions. He never mentioned HDL/TG ratio, but it certainly appears that would apply.

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Re: Plasmalogens- exciting new evidence

Postby Orangeblossom » Sun Feb 18, 2018 10:25 am

Julie G wrote:
So how can we check these levels? I note it is plasma levels as well, not levels in the brain...Would it relate to or be indicated by HDL / trigs ratio?

Dayan (like Rasmussesn with APOE) is using plasma levels. The testing is not particularly difficult, but unfortunately not widely available. Once again, slide #73 answers your questions. He never mentioned HDL/TG ratio, but it certainly appears that would apply.


OK that sounds hopeful. So it seems the plasma levels are a useful measure here. Yes I can confirm that with dietary changes and increased exercise my levels are quite similar:, HDL 108, Trigs 69, LDL 70 and HDL:LDL ratio 1.6 so hopefully that is going in the right direction.

It is interesting to note from the slides that in the highest Pls1 group, the LDL and total cholesterol are also high as well, too. What are PBV and TAG anyone know? PBV may be parts by volume of the plasmalogens, perhaps looking at the levels?

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Re: Plasmalogens- exciting new evidence

Postby Julie G » Sun Feb 18, 2018 11:55 am

It is interesting to note from the slides that in the highest Pls1 group, the LDL and total cholesterol are also high as well, too.
Yeah, Marc questioned that because Dayan asserted (despite his data) that low LDL was preferable. He cautioned us against literally applying the LDL/TC information presented in the graphs. Earlier in the presentation he said that cholesterol makes cell walls stiff; whereas DHA makes them fluid. It's worth noting that many of us use non-cholesterol dietary fats (EVOO, avocados, nuts) that also contribute to elevated LDL. I couldn't help but wonder if his LDL/TC cautions were grounded in the lipid hypothesis?
What are PBV and TAG anyone know? PBV may be parts by volume of the plasmalogens, perhaps looking at the levels?

PBV is plasmalogen biosynthesis value; likely an internal term for plamalogen level (?) TAG is triglycerides.

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Re: Plasmalogens- exciting new evidence

Postby Searcher » Sun Feb 18, 2018 12:36 pm

Some other good natural sources of plasmalogens :

Lamb brain (18 mg/g)
Mussels (2.5 mg/g)

Plasmalogens survive passage through the stomach better if the gastric acidity is limited, such as by a fatty meal.

Plasmalogen supplements are already marketed in the Far East, for Alzheimer's.

http://www.oilsfats.org.nz/wp-content/u ... v-2016.pdf

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Re: Plasmalogens- exciting new evidence

Postby Orangeblossom » Sun Feb 18, 2018 1:23 pm

Don't really fancy the brains etc! I see egg yolks are relatively good sources and also high in choline so might be a plan. I get these Omega 3 rich eggs where the hens are free range and fed on a Omega 3 rich diet- the yolks are really orange.

I found this article here which was quite useful on plasmalogens-

Functions of plasmalogen lipids in health and disease
https://www.sciencedirect.com/science/a ... 3912001160

Alzheimer disease (AD)

The pathophysiology of AD involves several factors including the accumulation of neurofibrillary tangles (NFT), composed of intracellular tau bodies, accumulation of extracellular amyloid β peptide (Aβ) plaques and synaptic loss [82]. Oxidative and inflammatory damage pursue. Although the only predictive factor for AD aside from age is an ApoE4 genotype, an increasing number of studies has shown that plasmalogen deficiency, as well as generalized peroxisome dysfunction, may also be a specific marker for AD pathology. Thus far there has been no correlation between plasmalogen deficiency and ApoE genotype, implicating that plasmalogen deficiency is an independent marker [83].

AD patients have decreased PlsEtn and PlsCho in affected brain regions and the extent of reduction is correlated to severity of disease [84,85]. This selective plasmalogen decrease was not found in autopsy brain samples from patients with Huntington's or Parkinson's disease. Han et al. [6] correlated the plasmalogen deficiency in AD with the patient's clinical dementia stage. The investigators found a dramatic decrease of up to 40 mol% in plasmalogen content of white matter at early AD stages, and a decrease of 10 mol% in gray matter at early stages and 30 mol% in severe dementia. Wood et al. [86] showed that erythrocyte plasmalogen levels also correlated to disease severity implying a systemic etiology for plasmalogen reduction.

Kou et al. [87] noted more extensive peroxisome-related alterations in AD brain utilizing samples from a prospective study of aging individuals. This unique study design, in which one brain hemisphere was staged pathologically and the other studied biochemically, allowed direct correlation between biochemical findings and amounts of NFT and plaques. These investigators found increased very long chain fatty acids, decreased plasmalogens containing polyunsaturated fatty acids, increased peroxisome volume density in neuronal cell bodies and decreased peroxisome numbers in neurites. These changes showed a stronger association with tau, rather than Aβ, accumulation. Although both are hallmarks of AD, NFT correlate better with disease pathology, strengthening the association of reduced peroxisome functions with AD progression. Thus reduced plasmalogens may be related to decreased synthesis secondary to general loss of peroxisome functions in AD brain. In this regard, Grimm et al. [88] showed that increased Aβ reduces AGPS protein levels. Reduction in DHA levels observed in AD brain [89], could result from deficient plasmalogens. Furthermore, reduced synthesis of DHA was shown in AD liver, suggesting decreased synthesis of these precursors in the liver, as well as brain.

Loss of plasmalogens in the AD brain could also occur through oxidative damage, leading to plasmalogen degradation by ROS species. In addition, increased catabolism of plasmalogens was suggested by the finding of elevated plasmalogen specific PLA2 from the nucleus basalis and hippocampal regions of AD brain [90,91]. This correlates to the observed increase in lipid remodeling, as well as reduced levels of DHA and AA in brain plasmalogen fractions [84,87].

Reduced plasmalogens might further enhance ongoing oxidative damage in AD, as well as alter membrane properties to promote further damage. The lipid environment affects APP processing, as its processing enzymes are integral membrane proteins and the Aβ cleavage takes place within the membrane. Increased membrane free cholesterol increases the production of Aβ from amyloid precursor protein (APP), whereas cholesterol esters stimulate non-amyloidogenic APP degradation [92]. Plasmalogen deficiency, which results in higher membrane free cholesterol, would thus facilitate Aβ production. Furthermore, Aβ aggregation can be modulated by plasmalogens. Using a sensitive fluorophore assay, Lee et al. [93] showed that, when Aβ was incubated with unilamellar vesicles composed of 1-(1Z-octadecenyl)-2-arachidonyl-sn-GPEtn, there was inhibition of oligomer formation and sluggish fibril formation. Depletion of neuroprotectin D1, a bioactive molecule derived from DHA, may also have a role in Aβ accumulation [94]. Finally, loss of gray matter plasmalogens would be expected to adversely affect synaptic structure and function, thus potentially contributing to the synaptic dysfunction and neurotransmitter depletion observed in AD.

4.12. Lipid signaling and disease states

Imbalances of major lipid signaling pathways contribute to disease progression in chronic inflammation, metabolic syndrome, type II diabetes, neurodegenerative and cardiovascular diseases. Increased lipid oxidation accompanies these pathological states and is associated with decreased plasmalogen levels.

Plasmalogens are enriched in nascent lipoproteins secreted by cultured rat hepatocytes where they may serve as endogenous plasma antioxidants [8]. Colas et al. [95] evaluated LDL from obese patients with metabolic syndrome and patients with type II diabetes and found decreased PlsEtn levels (22% and 49% respectively), increased lipid peroxidation, decreased cholesterol ester and increased triglyceride compared to controls. PlsEtn levels were also found to be decreased by 20% in erythrocyte membranes from hyperlipidemic patients.

Leukocyte myeloperoxidase generates hypochlorous acid (HOCl) from hydrogen peroxide and chloride gas, as part of immune defense reactions. Plasmalogens, already enriched in leukocytes, are one of the primary targets of HOCl due to sensitivity of the vinyl ether bond to oxidants. The rate constants for HOCl dependent plasmalogen modification are around 10 fold higher than their diacyl GP counterparts [96]. The direct products, α-chloro fatty aldehyde and 1-lyso-2-acyl-sn-GP (Fig. 3), may produce a family of chlorinated lipids that can regulate inflammatory responses [4]. Monocyte infiltration into atherosclerotic vascular wall and into myocardial infarct zones is associated with the accumulation of the α-chloro fatty aldehyde, 2-chlorohexadecanal, in these tissues. Similarly, neuroinflammation results in the accumulation of 2-chlorohexadecanal in brain lipids of endotoxin treated mice [97]. Thus inflammatory conditions may deplete plasmalogen levels.

In myocardial ischemia, there is early activation of plasmalogen specific PLA2, leading to plasmalogen loss. The provision of chimyl alcohol to isolated rat hearts reduced reperfusion injury following ischemia as measured by increased left ventricular function and coronary flow, reduced creatine kinase release and decreased lipid peroxidation [98]. This study suggested that increased plasmalogen levels, secondary to chimyl alcohol supplementation, might protect against ischemic damage. Furthermore, plasmalogens may have additional functions in cardiac sarcolemma, where they are enriched. Ford and Hale [99] showed preferred reconstitution of the trans-sarcolemmal Na+–Ca2+ exchanger (SLC8A1) in phospholipid vesicles containing plasmalogens as compared to diacyl GP alone, suggesting a structural role for plasmalogens.

5. Plasmalogen replacement therapy
Plasmalogen replacement therapy would be of substantial benefit in RCDP, and may also be of benefit in disorders that feature secondary plasmalogen deficiency. Although plasmalogens are mostly biosynthesized, small amounts can be obtained from dietary compounds [100]. The highest amounts are found in oils of invertebrate marine animals, such as shark liver and krill oil [101]. The average adult is estimated to consume 10–100 mg of 1-0-octadecyl-sn-glycerol (batyl alcohol) daily [102]. Although it is the alkylglycerol content of these dietary compounds that has been more extensively studied, there is some evidence that intestinal absorption of phospholipids is superior to that of alkylglycerols [101].

Dietary alkylglycerols are absorbed intact, however the ether bond can be subsequently oxidized in intestinal mucosal cells [103]. As summarized by Das et al. [104] in rodent feeding studies, only 1-0-alkylglycerols, saturated or monounsaturated, of appropriate chain length (C15-19) can be incorporated into plasmalogens. Administration of 1–2% 1-0-heptadecyl-sn-glycerol in feeds to growing rats resulted in a 40–60% incorporation of the targeted C17 moiety at the C1 position of PlsEtn in most tissues and an increase in the alkylglycerol content, but no change in total plasmalogen content [104]. Thus the alkyl composition of plasmalogens can be altered by dietary supplementation, but the total tissue plasmalogen amount remains unchanged, perhaps reflecting control by FAR1.

Nevertheless, the vast majority of endogenous mammalian plasmalogens contain only C16:0, C18:0 and C18:1 alkyl chains. Plasma lipids reflect dietary changes over a period of days, whereas changes in erythrocyte and other tissue lipids occur over several weeks [105]. 1-0-Heptadecyl-sn-glycerol was not incorporated into tissues of newborn mouse pups after supplementation of mothers for most of the gestational period, indicating that ether lipids are not transported across the placenta to the fetus [104]. Transfer through lactation was observed, but was less efficient than direct consumption from foods. There was also low incorporation into brain, either because alkylglycerols do not efficiently cross the blood brain barrier, or because of high turnover in brain.

Since the plasmalogen precursor, 1-0-alkylglycerol, enters the plasmalogen biosynthetic pathway downstream of the peroxisomal steps (Fig. 2), it may help recover plasmalogen levels in Zellweger spectrum and RCDP patients. Recovery of tissue plasmalogen levels and various cell dependent functions after alkylglycerol supplementation has been reported using patient fibroblast cell lines, as discussed above. Several case reports show improvement in erythrocyte plasmalogen levels in PBD patients after batyl alcohol supplementation [104,106,107]. Brites et al. [108], using a PEX7 null mouse model, showed that high doses (around 400 mg/kg) and early supplementation were required for maximal clinical efficacy. Reduced transport across the placenta and through lactation was confirmed. Although plasmalogen levels could be recovered and tissue pathology improved in somatic tissues, this was not the case in brain, in which only around 1% of control plasmalogens were present after 2 months of treatment, and around 2% at 4 months of treatment.

Wood et al. [109] synthesized an alkyl-diacyl plasmalogen precursor, 1-0-hexadecyl-2-DHA-sn-lipoic acid on the basis that lipoic acid stabilized the oral precursor, and that tissue deficiencies of plasmalogens containing DHA could be more effectively targeted. Using their plasmalogen precursor in RCDP cell lines, these investigators showed recovery of the target, 1-0 (1Z-hexadecyl-2-DHA-sn-GPEtn as well as other 1-0 (1Z-hexadecyl)-2-acyl-GPEtn species, indicating active remodeling at sn-2. Evaluation of reduced plasmalogen species in a PEX7 hypomorphic mouse model showed the most dramatic decrements in species containing DHA, especially in brain and eye [110]. After specific labeling of this plasmalogen precursor and providing it by gavage at 100 mg/kg for 3 days, Wood et al. [110] showed around a 10 fold increase in incorporation of the target plasmalogen into brain and eye of PEX7 hypomorphic mice, and around a 4 fold increase in adrenal, kidney and lung tissues compared to controls. Thus greater uptake was obtained in plasmalogen deficient tissues. Overall, these studies indicate that sustained treatment periods with plasmalogen precursors will be needed to overcome turnover and reach steady state physiological levels in brain. These reports also demonstrated that rearrangement at the 1-0-alkyl group does not occur, and therefore the naturally occurring alkylglycerols, chimyl alcohol, batyl alcohol and 1-0-octadecenyl-sn-glycerol (selachyl alcohol), would need to be provided together in order to recover each plasmalogen class.

6. Concluding remarks
Plasmalogens, by virtue of their vinyl ether bond and enrichment in DHA and AA, play a critical role in cell membranes— providing unique structural attributes, facilitating signaling processes and protecting membrane lipids from oxidation. As these factors are particular to different tissue types, plasmalogen functions are likely to be tissue and developmental stage specific. The peroxisome disorder, RCDP, reveals their roles in organ development, whereas secondary plasmalogen deficiency disorders reveal roles in tissue homeostasis. A number of useful studies have been done at the cellular level to investigate plasmalogen functions. The current availability of RCDP mouse models should enable us to more quickly evaluate these in tissue and organ systems. Furthermore, the elucidation of the spectrum of plasmalogen subspecies by LC/MSMS will contribute to better understanding of plasmalogen biology. Finally, there is a need to determine how to improve the uptake of plasmalogen precursors into the central nervous system."

A bit of a read there, sorry! :? All seems quite complex.


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