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Friday, 30 March 2018

Autism and Aspartic Acid - N-acetylaspartate (NAA), AGC1, CREB and EAAT1/2



Aspartic acid is a metabolite of the sweetener Aspartame; not a surprise when you taste it

Today’s post is about the amino acid aspartic acid, which our reader Tyler has been supplementing. The short version of this post would answer the question should we all follow Tyler and supplement L-Aspartic acid? I guess the answer is that it is well worth a trial.
There is a great deal of complex science showing that aspartic acid is dysfunctional in autism, but we cannot prove that supplemental aspartic acid corrects these dysfunctions. Supplemental aspartic acid will have other effects and it may be these that are beneficial in Tyler’s case and possibly yours.
Correcting the core dysfunctions relating to Aspartic acid would be very helpful, if it were possible.  You could write an entire book just about the contents of today’s post, so for most people understanding all of it will take quite some time.

You can read Tyler’s many comments on this subject by entering the following into google.

       aspartate "site:epiphanyasd.blogspot.com"

This gives you a list of those posts, where he left comments on aspartate.
Then press the “crtl” key and the “f” key and this will find the mentions of “aspartate” in that post and its comments

Here are some comments.





Malate-Aspartate Shuttle
I wonder if the reason supplemental aspartic acid may help some people comes from something called the Malate-Aspartate Shuttle.  Now this does get complicated, but is links together many things we already know:-
·        Disturbed calcium channel signaling and excess physical calcium in autistic brains

·        Abnormal myelination

·        Oxidative stress

·        Mitochondrial abnormalities

·        Microglial activation

·        Disturbed BDNF, VEGF, CRH etc.

There is also a very interesting potential protective genetic variation (SLC25A12) that appears to protect some siblings from developing autism.
It appears that the excessive level of (cytosolic) Ca2+ increases the expression of AGC1 (the mitochondrial aspartate/ glutamate carrier number 1) via CREB (cAMP response element-binding protein).
CREB is a cellular transcription factor that regulates numerous genes including c-fos, BDNF, tyrosine hydroxylase, numerous neuropeptides (somatostatin, enkephalin, VGF, corticotropin-releasing hormone CRH, etc.), and genes involved in the circadian clock (PER1, PER2). 

For instance, multiple stimuli induce the phosphorylation of the cyclic AMP-responsive element-binding protein (CREB) at Ser-133, which recruits the CREB-binding protein (CBP) to gene promoters. CBP catalyses the acetylation of histones, leading to changes in chromatin structure that facilitate the recruitment of RNA polymerase II and the activation of gene-transcription programs that promote synapse development12,15.
In addition to stimulating CREB-dependent gene transcription, neuronal activity-dependent calcium influx into neurons triggers the dephosphorylation of the transcription factor myocyte enhancer factor 2 (MEF2) by calcineurin, disrupting the association of MEF2 with histone deacetylases and leading to the recruitment of CBP and the stimulation of gene transcription26. 


Neuronal activity that functions through CREB, MEF2 and multiple other activity-regulated transcription factors — including SRF, Fos27 and NPAS428 — induces the transcription of the genes encoding proteins that function directly at synapses, including Bdnf, Arc and Ube3A12,15.
For example, activity-regulated MEF2 by activating Arc suppresses the number of excitatory synapses26,29, whereas CREB and NPAS4, by activating Bdnf transcription, control the number of inhibitory synapses that form on excitatory neurons28,30.

CREB is down regulated in Alzheimer’s.
CREB proteins are activated by phosphorylation from various kinases, including PKA.
A number of existing drugs can raise or lower PKA levels in the body. 
You would want to raise PKA in Alzheimer’s and some autism.
If AGC1 is over-activated this could be corrected using a PKA inhibitor, but this is easier said than done.  PKA does very many different things.
PDE4 inhibitors used to treat asthma and COPD (Ibudilast and Daxas) raise PKA.
PDE4 inhibitors also reduce microglial activation. See the reference to gliosis below.
As our reader Nat knows, Ca2+ ions are the source of numerous problems in autism.  The route problem seems to be too much calcium released from the stores within each cell (endoplasmic reticulum) and/or faulty voltage gated calcium channels allowing Ca2+ to enter from outside the cell.
The malate-aspartate shuttle “functions to move reducing equivalents into the mitochondrial matrix in the form of malate, whereas the major mitochondrial output through this complex is aspartate”. Specifically, AGC1 moves cytoplasmic glutamate into mitochondria, while moving mitochondrially synthesized aspartate out. Without AGC1, brain mitochondrial glutamate import and aspartate export are crippled. Studies with AGC1 knockout mice showed a dramatic drop in brain aspartate levels, with a concomitant reduction in NAA (N-acetylaspartate) synthesis.
AGC1 activation increases mitochondrial metabolism and oxidative stress
Reduction in N-acetylaspartate (NAA) synthesis causes hypomyelination.
N-acetylaspartate (NAA) is synthesized from acetyl CoA and aspartate. NAA is very important in the brain; too little NAA causes reduced myelination (hypomyelination) which is a feature of autism. Studies show that NAA is reduced in the brains of young people with autism, but interestingly not in older people with autism.
In autism we expect to see activated AGC1 and reduced NAA
It does look like NAA is something you do not want to be deficient in, but you also do not want too much. NAA is synthesized from acetyl CoA and aspartate and without going into details you might just say, why not just add some extra aspartate, which you can buy as an OTC powder. 
There is a very more complex explanation, which comes back to aberrant calcium signaling being the demon of most autism. That would suggest:-
“Pharmacological treatments able to modulate extracellular Ca2+ entry, intracellular Ca2+ release from the endoplasmic reticulum or putative upstream immune mechanisms affecting either or both the pathways are, at least in principle, already available”

Overexpression of mitochondrial aspartate/glutamate carrier AGC1/ aralar1 (annoyingly, some research use the term  Aralar1 while others use AGC1) encoded by encoded by the SLC25A12, caused by excess calcium Ca2+ either from intracellular release from stores in the endoplasmic reticulum or extracellular Ca2+. Recall the post about Gargus’ theory that a key nexus in autism is the IPR3 receptor,  in the Endoplasmic Reticulum within each cell. He believes this is core defect in much autism.

Canavan disease is a rare condition caused by far too much NAA, a genetic error prevents the normal breakdown of NAA and this disrupts myelination leading to death in childhood.

Also part of the malate-aspartate shuttle we have GLutamate ASpartate Transporter (GLAST) or Excitatory Amino Acid Transporter 1 (EAAT1). We know that both glutamate transporters EAAT1 and EAAT2 are over-expressed in the cerebellum of post-mortem tissue from autism patients.  Because EAAT expression is controlled in part by the extracellular concentration of glutamate, it is possible that the EAAT overexpression is due to the increased glutamate concentration seen in plasma and spectroscopic studies.

Glutamate & Glutamine
Since I have mentioned glutamate, note that numerous studies show high levels of glutamate but low levels of its precursor glutamine in autism. Gliosis is one possible explanation. This connects with those activated microglia which are another recurring feature of autism:-


“An increase in gliosis, which is characterized by enhanced activation of astrocytes and microglia, has been observed in the brains of individuals with autism. Interestingly, Ortinski et al. have reported that activated astrocytes downregulate the expression of glutamine synthetase, whereby glutamate is converted into glutamine, which in turn results in reduced glutamine coupled with elevated glutamate. In addition, glutaminase, another enzyme related to glutamate/glutamine metabolism via its conversion of glutamine into glutamate, has been shown to be upregulated in activated microglia. Thus, it is tempting to assume that the process of gliosis generation may be related to the etiology of autism, as mediated by activated astrocytes and/or activated microglia, which may disturb the regulation of certain types of enzymes and thereby alter the metabolism of glutamate/glutamine. Taken together with previous findings, our results demonstrating glutamate/glutamine abnormalities in the plasma of individuals with autism may be indicative of a gliosis process in the autistic brain.

Amino Acids and the BBB
Amino acids are present inside the brain but some do not cross easily across the BBB. If they do not cross the BBB then taking a supplement is not going to help much.
This point is quite relevant because one study showed that arginine deprivation plays a key role in Alzheimer’s, but the mass media pointed out that taking arginine supplements is not going to help. Had they read this blog they would have known that if you want to increase arginine in the brain, you want to take citrulline. So citrulline for Alzheimer’s?  well worth investigating.  
The amino acid transporters that control the level in the brain are themselves disturbed in autism. So it may be that the level of many amino acids in autistic brains is disturbed, regardless of diet and what the blood/urine levels indicate.

Amino acid gradients between brain and plasma





Amino acid concentrations in plasma and brain. The plasma and CSF concentrations were grouped and the CSF-to-plasma ratio expressed as percent of the plasma. CSF concentrations are assumed to approximate brain ECF (54,102). With the exception of glutamine, the concentrations of all AAs in the ECF are much lower than the concentrations of AAs in plasma.


The concentrations of all naturally occurring AAs in the cerebral spinal fluid (CSF) (presumably similar to the extracellular fluid (ECF) of the brain), with the exception of glutamine, are 10% or less than the plasma concentrations (Fig. 4) (54). This situation cannot be explained by the consumption of AAs by brain because the arteriovenous differences across brain of most AAs are imperceptible (55–57), as are the arteriovenous differences of ammonia (NH4+), a byproduct of AA catabolism (58). These observations indicate that AAs leave the brain against a concentration gradient. From this it may be concluded that active (e.g., Na+-dependent) systems on the abluminal membrane have an important role in maintaining both homeostasis of brain AA content as well as the lower concentration in the extracellular fluid. Based on similar observations Bradbury wrote “there is a strong indirect argument in favor of the hypothesis that most AA must be moved against a concentration gradient from interstitial fluid to blood” (34).



The present view of the BBB is that cerebral endothelial cells participate actively in regulating the composition of brain extracellular fluid and the AA content of the brain. The luminal and abluminal membranes work in a complementary fashion with the Na+-dependent transport of AAs occurring at the abluminal membrane, and with facilitative transport at the luminal membrane, or, in the case of LNAAs, at both membranes (97).

Although the BBB determines the availability and therefore the brain content of essential AAs, astrocytes and neurons participate in maintaining the extracellular concentrations. Astrocytes and neurons have Na+-dependent transport systems capable of transporting NAAs and acidic AAs (98–100). These systems are actively involved in regulating AA concentrations in ECF and are especially important in the maintenance of low concentrations of neurotransmitter AAs such as glutamate, aspartate, and glycine. On the other hand, it now seems clear that the BBB also participates in the active regulation of brain ECF composition, and the abluminal membrane is especially important in this role.

Characteristics of L-citrulline transport through blood-brain barrier in the brain capillary endothelial cellline (TR-BBB cells)


Background

L-Citrulline is a neutral amino acid and a major precursor of L-arginine in the nitric oxide (NO) cycle. Recently it has been reported that L-citrulline prevents neuronal cell death and protects cerebrovascular injury, therefore, L-citrulline may have a neuroprotective effect to improve cerebrovascular dysfunction. Therefore, we aimed to clarify the brain transport mechanism of L-citrulline through blood-brain barrier (BBB) using the conditionally immortalized rat brain capillary endothelial cell line (TR-BBB cells), as an in vitro model of the BBB. 

Conclusions

Our results suggest that transport of L-citrulline is mainly mediated by LAT1 in TR-BBB cells. Delivery strategy for LAT1-mediated transport and supply of L-citrulline to the brain may serve as therapeutic approaches to improve its neuroprotective effect in patients with cerebrovascular disease.
Our results demonstrated that L-citrulline transport might be mainly mediated by LAT1 in TR-BBB cells. Understanding the transport characteristics of L-citrulline to the brain through BBB might contribute to the transport strategy for L-citrulline as a potential therapeutic agent for cerebrovascular diseases such as brain ischemia. 



Disturbed amino acid transporters and levels in blood/urine      

Since we know that the amino acid transporters that carry amino acids across the blood brain barrier are disturbed in autism what is the relevance of blood/urine tests and standard reference levels? Unless you lest amino acid levels in spinal fluid (i.e. within the central nervous system) do lab tests really help? You certainly need to be aware of their limitations.
So as you can see even the summary is highly complicated.
Very many things associated with aspartate are messed up in autism and Tyler finds his son benefits from L-aspartate supplementation.
We saw in an earlier post that NT girls had three times the level of excreted aspartic acid than NT boys and that people with autism had very low levels of excreted aspartic acid.
If you could fix the underlying problem with elevated Ca2+ as proposed by Gargus, you would solve the AGC1/NAA problem. It may be that by supplementing L-aspartate you do have an effect on the  malate-aspartate shuttle, even though there is no solid understanding of exactly how this occurs.







IP3R controls the release of calcium from the ER (Endoplasmic Reticulum inside each cell). In the brain, calcium is used to communicate information within and between neurons, and it activates a host of other cell functions, including ones regulating learning and memory, neuronal excitability and neurotransmitter release – areas known to be dysfunctional in ASD. It also causes the release of Protein Kinase C which then acts to change the function of numerous proteins (via phosphorylation) and trigger a series of signaling cascades.

Rapid progress in our understanding of macrostructural abnormalities in autism spectrum disorders (ASD) has occurred in recent years. However, the relationship between the integrity of neural tissue and neural function has not been previously investigated. Single-voxel proton magnetic resonance spectroscopy and functional magnetic resonance imaging of an executive functioning task was obtained in 13 high functioning adolescents and adults with ASD and 13 age-matched controls. The ASD group showed significant reductions in N-acetyl aspartate (NAA) in all brain regions combined and a specific reduction in left frontal cortex compared to controls. Regression analyses revealed a significant group interaction effect between frontal and cerebellar NAA. In addition, a significant positive semi-partial correlation between left frontal lobe NAA and frontal lobe functional activation was found in the ASD group. These findings suggest that widespread neuronal dysfunction is present in high functioning individuals with ASD. Hypothesized developmental links between frontal and cerebellar vermis neural abnormalities were supported, in that impaired neuronal functioning in the vermis was associated with impaired neuronal functioning in the frontal lobes in the ASD group. Furthermore, this study provided the first direct evidence of the relationship between abnormal functional activation in prefrontal cortex and neuronal dysfunction in ASD.
This study extended prior work in this area by establishing that neural abnormalities, which have been identified using 1H-MRS predominantly in younger and likely lower functioning autistic individuals), may also be present in a higher functioning broadly inclusive ASD sample. None of the individuals in our sample had IQs in the mentally retarded range and the sample included individuals with diagnoses in the less severe end of the autism spectrum; approximately 43% of the sample was diagnosed as PDD-NOS or Asperger’s disorder. 
Recent postmortem studies have identified neuroinflammation as a compelling potential pathological mechanism for reduced levels of NAA in individuals with ASD (Laurence and Fatemi, 2005; Vargas et al., 2005). Vargas and colleagues documented microglial activation in postmortem middle frontal gyrus, anterior cingulate, and cerebellar tissue, and in cerebral spinal fluid (CSF) of children and adults with autism. Laurence and Fatemi found increased glial fibrillary acidic protein in area 9, area 40 and the cerebellum in autism. Ongoing neuroinflammatory processes may produce alterations in brain tissue that would result in reduced NAA (secondary to cell loss or damage), as was observed in the current study. 
We found that high functioning individuals with ASD have reduced levels of NAA compared to age-matched controls. The most consistent area of abnormality was observed in the left middle frontal gyrus. In addition, the relationship between level of NAA in the frontal lobes and NAA in the cerebellar vermis differed between groups. These findings of biochemical alterations in ASD may reflect early brain growth dysregulation and ongoing neuroinflammatory processes. Reduced levels of NAA in ASD were also directly related to neurofunctional abnormalities observed in the FMRI study of executive functioning. This study is the first to directly link functional activation to neuronal integrity in ASD, and provides direct evidence that primary neuronal dysfunction, in addition to hypothesized aberrant neural connectivity leads to neurofunctional impairment in high functioning individuals with autism spectrum disorders. 


Atypical trajectory of brain growth in autism spectrum disorders (ASDs) has been recognized as a potential etiology of an atypical course of behavioral development. Numerous neuroimaging studies have focused on childhood to investigate atypical age-related change of brain structure and function, because it is a period of neuron and synapse maturation. Recent studies, however, have shown that the atypical age-related structural change of autistic brain expands beyond childhood and constitutes neural underpinnings for lifelong difficulty to behavioral adaptation. Thus, we examined effects of aging on neurochemical aspects of brain maturation using 3-T proton magnetic resonance spectroscopy (1H-MRS) with single voxel in the medial prefrontal cortex (PFC) in 24 adult men with non-medicated high-functioning ASDs and 25 age-, IQ- and parental-socioeconomic-background-matched men with typical development (TD). Multivariate analyses of covariance demonstrated significantly high N-acetylaspartate (NAA) level in the ASD subjects compared with the TD subjects (F=4.83, P=0.033). The low NAA level showed a significant positive correlation with advanced age in the TD group (r=−0.618, P=0.001), but was not evident among the ASD individuals (r=0.258, P=0.223). Fisher's r-to-z transformation showed a significant difference in the correlations between the ASD and TD groups (Z=−3.23, P=0.001), which indicated that the age–NAA relationship was significantly specific to people with TD. The current 1H-MRS study provided new evidence that atypical age-related change of neurochemical aspects of brain maturation in ASD individuals expands beyond childhood and persists during adulthood.



In conclusion, the present findings demonstrated an absence of typical age-related medial prefrontal NAA decrement in ASD individuals during adulthood. Such an atypical relationship between age and NAA levels might contribute to a significant NAA increase in the ASD subjects compared with the TD adults. Although future studies should examine potential localization of atypical age-related NAA change and longitudinal course of autistic NAA abnormality, the current study has provided a new suggestion with regard to a role of atypical age-related NAA changes in the pathophysiology of ASD.


An interesting way to increase NAA:-

Supplement 'boosts' brain power
"They were asked to be more active and cut down on unhealthy snacks and fizzy drinks. 

At the same time, they were given two capsules a day of the VegEPA supplement, which contains an omega-3 fatty acid called EPA.

Tests done at the end of the three-month study found the children showed an increase in reading age of well over a year, their handwriting became neater and more accurate and they paid more attention in class.

Brain scans which identified a chemical called N-Acetylaspartate (NAA) which is linked to the growth of nerve fibres in the brain also showed dramatic changes, said Professor Puri.

Although the children were encouraged to change their diet, there was no evidence they did this to any great extent, suggesting the improvements in the children were a result of the supplement.


Brain growth 

"In three months you might expect to see a small NAA increase.

"But we saw as much growth as you would normally see in three years.

"It was as if these were the brains of children three years older. It means you have more connections and greater density of nerve cells, in the same way a tree grows more branches."

The boys in the study showed the most improvement, he added.

Omega-3 fatty acids are found naturally in oily fish such as mackerel, salmon, herring and tuna or seeds such as flax, pumpkin and hemp.

A systematic review of fish oil supplements in children published by the Food Standards Agency last year found there were too many inconsistencies in current evidence to come to any conclusion.

Professor Puri said he believed that it was EPA specifically which conferred the benefits which was why studies of fish oil supplements which also contain a fatty acid called DHA showed confusing results.

He is now planning to carry out a larger placebo-controlled study.

Professor Robert Grimble, professor of nutrition at the University of Southampton said it was vital that larger studies were done to clarify the issue.

"My view is we can't come to any clear conclusion until a proper trial is done.

"These small bits of weak data just confuse the public. The FSA looked at this very carefully and I wouldn't contradict that until we have more evidence." 



N-Acetylaspartate (NAA) is employed as a non-invasive marker for neuronal health using proton magnetic resonance spectroscopy (MRS). This utility is afforded by the fact that NAA is one of the most concentrated brain metabolites and that it produces the largest peak in MRS scans of the healthy human brain. NAA levels in the brain are reduced proportionately to the degree of tissue damage after traumatic brain injury (TBI) and the reductions parallel the reductions in ATP levels. Because NAA is the most concentrated acetylated metabolite in the brain, we have hypothesized that NAA acts in part as an extensive reservoir of acetate for acetyl coenzyme A synthesis. Therefore, the loss of NAA after TBI impairs acetyl coenzyme A dependent functions including energy derivation, lipid synthesis, and protein acetylation reactions in distinct ways in different cell populations. The enzymes involved in synthesizing and metabolizing NAA are predominantly expressed in neurons and oligodendrocytes, respectively, and therefore some proportion of NAA must be transferred between cell types before the acetate can be liberated, converted to acetyl coenzyme A and utilized. Studies have indicated that glucose metabolism in neurons is reduced, but that acetate metabolism in astrocytes is increased following TBI, possibly reflecting an increased role for non-glucose energy sources in response to injury. NAA can provide additional acetate for intercellular metabolite trafficking to maintain acetyl CoA levels after injury. Here we explore changes in NAA, acetate, and acetyl coenzyme A metabolism in response to brain injury
N-acetylaspartate (NAA) is one of the most abundant brain metabolites and is highly concentrated in neurons, but it remains to be determined why neurons synthesize so much of this particular acetylated amino acid. Early research implicated NAA in lipid synthesis in the brain, especially during postnatal myelination.
NAA is synthesized from acetyl CoA and aspartate, and because of the exceptionally high concentration in the human brain (~10 mM) some proportion of acetyl CoA must be utilized to maintain NAA levels 
The primary mitochondrial aspartate-glutamate carrier expressed in brain, heart, skeletal muscle, and several other tissues is known as aralar1 (Del Arco et al., 2002), which is part of a larger complex that comprises the so-called mitochondrial malate-aspartate shuttle. The malate-aspartate shuttle functions to move reducing equivalents into the mitochondrial matrix in the form of malate, whereas the major mitochondrial output through this complex is aspartate. Specifically, aralar1 moves cytoplasmic glutamate into mitochondria, while moving mitochondrially synthesized aspartate out. Without aralar1, brain mitochondrial glutamate import and aspartate export are crippled. Studies with aralar1 knockout mice showed a dramatic drop in brain aspartate levels, with a concomitant reduction in NAA synthesis
The connection between a lack of aralar1 expression and dramatically reduced NAA synthesis has at least two potential explanations. First, as suggested by Jalil et al. (2005) it could be due to the lack of mitochondrial aspartate output, which in turn would limit substrate availability for microsomal Asp-NAT to synthesize NAA. The other possible explanation is that the lack of glutamate uptake into neuronal mitochondria prevents intramitochondrial aspartate synthesis via the aspartate aminotransferase reaction which converts glutamate and oxaloacetate into α-ketoglutarate and aspartate. In this case the lack of intramitochondrial aspartate synthesis would be the limiting factor in NAA synthesis, leading to decreases in NAA levels. It is also possible that both of these mechanisms are responsible for the large drop in NAA levels observed in aralar1-deficient mice. 
One of the more interesting outcomes of aralar1 deficiency in addition to the large decrease in brain NAA levels is hypomyelination (Jalil et al., 2005; Wibom et al., 2009). The hypomyelination is hypothesized to result from the lack of availability of NAA and this conclusion is supported by the fact that galactocerebrosides, one of the myelin lipid classes that are reduced in Canavan disease 

The more NAA the more creative? 

A broadly accepted definition of creativity refers to the production of something both novel and useful within a given social context. Studies of patients with neurological and psychiatric disorders and neuroimaging studies of healthy controls have each drawn attention to frontal and temporal lobe contributions to creativity. Based on previous magnetic resonance (MR) spectroscopy studies demonstrating relationships between cognitive ability and concentrations of N-acetyl-aspartate (NAA), a common neurometabolite, we hypothesized that NAA assessed in gray and white matter (from a supraventricular slab) would relate to laboratory measures of creativity. MR imaging and divergent thinking measures were obtained in a cohort of 56 healthy controls. Independent judges ranked the creative products of each participant, from which a “Composite Creativity Index” (CCI) was created. Different patterns of correlations between NAA and CCI were found in higher verbal ability versus lower verbal ability participants, providing neurobiological support for a critical “threshold” regarding the relationship between intelligence and creativity. To our knowledge, this is the first report assessing the relationship between brain chemistry and creative cognition, as measured with divergent thinking, in a cohort comprised exclusively of normal, healthy participants.
Exactly how does variation in NAA concentration affect brain activity in normals? A rapidly growing literature links NAA to intelligence, working memory, attention, and memory both in health and disease (Ross and Sachdev, 2004), but the mechanisms underlying these relationships remain elusive. In the adult brain, there is substantial evidence that NAA is a marker of mitochondrial functioning, is involved in myelin lipid turnover, participates in axonglial signaling, and may be involved in brain nitrogen balance (Moffett et al., 2007). Substantial basic research has yet to unravel the complex role that NAA plays in higher cognitive functioning, including creativity, beyond mere correlation.

NAA is synthesized from acetyl CoA and aspartate, so you would not want to be short of either.





From your high school biology you may recall a process called aerobic respiration which is how you mitochondria convert Glucose (fuel) into ATP (energy).

As you can see one step in this process is the production of Acetyl CoA.

If you are breathing, you must be making Acetyl CoA.  So perhaps a little extra aspartic acid might help produce more NAA.

In extreme cases a lack of the mitochondrial carrier protein Aralar1 will causes very low levels of NAA. 

Canavan disease is a rare condition caused by too much NAA, a genetic error prevents the normal breakdown of NAA and this disrupts myelination leading to death in childhood.

Even after all that, we do not know for sure why supplementing Aspartate works for Tyler. Making more NAA would be a nice explanation but Aspartate does stimulate NMDA receptors.  


Autism is a severe developmental disorder, whose pathogenetic underpinnings are still largely unknown. Temporocortical gray matter from six matched patient-control pairs was used to perform post-mortem biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier (AGC), which participates in the aspartate/malate reduced nicotinamide adenine dinucleotide shuttle and is physiologically activated by calcium Ca2+. AGC transport rates were significantly higher in tissue homogenates from all six patients, including those with no history of seizures and with normal electroencephalograms prior to death. This increase was consistently blunted by the Ca2+ chelator ethylene glycol tetraacetic acid; neocortical Ca2+ levels were significantly higher in all six patients; no difference in AGC transport rates was found in isolated mitochondria from patients and controls following removal of the Ca2+-containing post mitochondrial supernatant. Expression of AGC1, the predominant AGC isoform in brain, and cytochrome c oxidase activity were both increased in autistic patients, indicating an activation of mitochondrial metabolism. Furthermore, oxidized mitochondrial proteins were markedly increased in four of the six patients. Variants of the AGC1-encoding SLC25A12 gene were neither correlated with AGC activation nor associated with autism-spectrum disorders in 309 simplex and 17 multiplex families, whereas some unaffected siblings may carry a protective gene variant. Therefore, excessive Ca2+ levels are responsible for boosting AGC activity, mitochondrial metabolism and, to a more variable degree, oxidative stress in autistic brains. AGC and altered Ca2+ homeostasis play a key interactive role in the cascade of signaling events leading to autism: their modulation could provide new preventive and therapeutic strategies.

Evidence linking altered energy metabolism to autistic disorder has been available for some time, including peripheral markers, such as increased plasma lactate levels, and rare instances of association between respiratory chain disorders and autism.  Interest in assessing the role of mitochondria

in this disorder has been revitalized by the association between autism and variants of the SLC25A12 gene, which encodes the predominant isoform of the mitochondrial aspartate (asp)/glutamate (glu) carrier (AGC) in brain.15,16 AGC belongs to a family of integral proteins that catalyze the transport of metabolites and cofactors across the inner mitochondrial membrane.17 In particular, AGC is important in energy metabolism

by transporting glutamate into mitochondria in exchange for matrix aspartate, a key regulatory step in the malate/aspartate reduced nicotinamide adenine dinucleotide (NADH) shuttle.18,19 Its two

isoforms, AGC1 and AGC2, also named aralar(1) and citrin, are encoded by the SLC25A12 and SLC25A13 genes, located on human chromosomes 2q24 and 7q21.3, respectively.19 AGC1 and AGC2 expression overlaps during early prenatal life, but diverges beginning in late gestation and into adulthood, with AGC1 predominantly expressed in the brain, heart and skeletal muscle, whereas AGC2 is mainly expressed in liver and kidney.20,21 In the CNS, AGC1 is highly expressed in neurons, whereas glial cells express both isoforms at much lower levels.20,21 Importantly, AGC activity is regulated by intracellular calcium (Ca2+) through four ‘EF-hand’ domains22 located at its N-terminus, hanging into the intermembrane

space.18,19 As Ca2+ concentrations in the mitochondrial intermembrane space and cytosol are in equilibrium, cytosolic Ca2+ can rapidly activate AGC transport, thereby increasing the NADH/NAD ratio in the mitochondrial matrix and consequently boosting electron flow through the respiratory

chain and adenosine triphosphate (ATP) generation by oxidative phosphorylation.18,19,23 Through this mechanism, AGC1 is important in the transduction of small Ca2+ signals to neuronal mitochondria.19 An

excessive amplitude and/or duration of Ca2+ spikes leading to AGC activation can, however, contribute to the formation of reactive oxygen species (ROS) and to oxidative stress.24 Genetic and/or environmental

factors could thus interfere with neuronal ATP production and with oxidative stress by affecting the AGC1 carrier, either directly or through Ca2+ homeostasis.



===================

Results

AGC activity is boosted by excessive Ca2+ levels in autistic brains

AGC activity, normalized by CS activity to adjust for differences in absolute mitochondria tissue content, displays a prominent threefold increase in neocortical homogenates from nonsyndromic autistic patients compared to matched controls in all six pairs (Wilcoxon’s test: Z=

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chelation by EGTA reduces asp/glu exchange rates to a much larger extent in patients than in controls (2.1- vs 0.35-fold, respectively), reducing case–control differences to only 36.1% (Figure 1a, middle). No difference between patients and controls is anymore detectable upon reconstitution of protein extracts from isolated mitochondria (P=0.17; Figure 1a, right). These results strongly point toward excessive Ca2+ concentrations as most likely responsible for increased asp/glu exchange rates in the brains of autistic patients.



AGC activation increases mitochondrial metabolism and oxidative stress

By increasing the availability of reducing equivalents in the mitochondrial matrix through AGC, enhanced cytosolic Ca2+ can be predicted to steadily boost mitochondrial metabolism and oxidative phosphorylation.18,19,23 Indeed, transcript amounts of the mitochondrial phosphate carrier (PiC), AGC1, and AGC2 (expressed at much lower levels compared to AGC1), are all increased (Supplementary Figure S2). Also COX activity is elevated to a similar extent in all six autistic patients compared to their matched controls (P<0 .05="" 3a="" figure="" span=""> 

No evidence of SLC25A12 gene contributions to autism vulnerability

Sequencing of the AGC1-encoding SLC25A12 cDNA and genomic DNA in these same six case–control pairs does not detect any nonsynonymous coding mutation
Figure 2 Calcium levels measured directly in the post mitochondrial supernatant by fluorimetry. (a) Calcium concentrations are significantly higher in the neocortical tissue of autism-spectrum disorder (ASD) patients compared to matched controls 

A SLC25A12 gene variant may confer protection in unaffected siblings

Single-marker analyses point toward the possible existence of a protective SLC25A12 gene variant preferentially transmitted from heterozygous parents to unaffected siblings of autistic patients.

The allele frequency of this haplotype is estimated at approximately 23–26% (Table 2b), making it a relatively common variant among unaffected siblings.
This study reports increased asp/glu exchange rates and significantly higher Ca2+ concentrations in postmortem neocortical tissue specimens of six nonsyndromic autistic patients compared to age-, sex- and PMI-matched controls. Altogether, our results strongly support excessive Ca2+ levels as primarily responsible for the observed activation of asp/glu exchange rates, whereas genetic contributions appear neither widespread nor necessary, at least in our postmortem and genetic samples.
Most importantly, direct measurements of neocortical Ca2+ concentrations clearly demonstrate a significant elevation of neocortical Ca2+ levels in all autistic patients compared to controls (Figure 2a)
Increased AGC transport rates, COX activities and Ca2+ levels consistently recorded in all six neocortical specimens from ASD patients crossvalidate each other, confirming the reliability and biological significance of these findings
In summary, altered Ca2+ homeostasis is the only factor shared by all autistic cortical tissue samples (Figure 2a), able to boost AGC activity,18,19,23 and previously linked to the pathogenesis of autism per se.
The existence of altered Ca2+ signaling in autism has been suggested in recent years by several lines of research.42 Gain-of-function mutations in the L-type voltage-gated Ca2+ channel Cav1.2 (CACNA1C) cause Timothy syndrome, a multisystem disorder including mental retardation and autism.43 Similarly, mutations in the L-type voltage-gated Ca2+ channel Cav1.4 (CACNA1F) cause the incomplete form of X-linked congenital stationary night blindness (CSNB2): gain-of-function mutations cause CSNB2 frequently accompanied by cognitive impairment and either autism or epilepsy, whereas CSNB2 due to lossof-function mutations is not accompanied by these symptoms.44 All of these gain-of-function mutations prevent voltage-dependent channel inactivation leading to excessive Ca2+ influx. Also mutations indirectly yielding increased cytosolic Ca2+ levels or amplifying intracellular Ca2+ signaling by hampering Ca2+-activated negative feedback mechanisms have been found associated with autism.42,45 The bioelectrical instability resulting from these mutations nicely parallels the high prevalence of seizures and/or EEG abnormalities present among autistic individuals 
We are currently in the process of correlating AGC activity and levels of oxidative stress with markers of immune activation, measured in the same tissue specimens assessed in this study. 
The present results can potentially pave the path to targeted preventive and therapeutic strategies. One important example is represented by thimerosal, an ethyl-mercury compound used as a preservative in vaccines.59,60 Thimerosal has drawn attention following initial anecdotal reports by some parents linking vaccinations to behavioral regression and to the onset of autism in their child within a matter of days or few weeks. Thimerosal is a Ca2+-mobilizing agent, capable of releasing Ca2+ from intracellular stores and increasing Ca2+ entry.61 Despite its short half-life compared to inorganic mercury, it undergoes preferential accumulation in the CNS, affecting the microglia and producing strain-dependent neurotoxic effects in rodents.62,63 This strain dependency, in conjunction with the present data, suggests that thimerosal could contribute to produce an unbalanced Ca2+ homeostasis in genetically vulnerable individuals. Indeed, a postnatal exposure to thimerosal is not reconcilable with the prenatal onset of neurodevelopmental anomalies leading to autism. Also large retrospective epidemiological studies confirm that thimerosal neither causes autism, nor provides large-scale contributions to its pathogenesis.2,60 However, our results suggest that thimerosal could conceivably precipitate an abrupt onset in a subset of children who would have otherwise developed autistic symptoms more insidiously. At the same time, we cannot exclude that thimerosal and other Ca2+-mobilizing environmental factors could also push genetically vulnerable individuals along the autism-spectrum toward more severe forms of the disease. On the basis of the present study, the elimination of thimerosal from vaccines, undertaken in the United States and Canada, is a well-justified safety measure. 

Pharmacological treatments able to modulate extracellular Ca2+ entry, intracellular Ca2+ release from the endoplasmic reticulum or putative upstream immune mechanisms affecting either or both the pathways are, at least in principle, already available. However, caution should be exercised in translating the present findings into therapeutic interventions prior to at least one replication in an independent cohort of brain samples and to assessments of Ca2+ homeostasis in vivo. 
Pharmacologically reducing Ca2+ entry into cells or blunting the oxidative damage produced by AGC activation seemingly represent more amenable and less dangerous therapeutic strategies. It is nonetheless difficult to predict the actual efficacy of treatments initiated during childhood on pathogenetic mechanisms active since early prenatal development. In this regard, the identification and functional characterization of protective SLC25A12 gene variants, if existent, could provide additional critical information on the contribution of AGC activation and oxidative stress to autism pathogenesis.

=======================

This study reports increased asp/glu exchange rates and significantly higher Ca2+ concentrations in postmortem neocortical tissue specimens of six nonsyndromic autistic patients compared to age-, sex- and PMI-matched controls. Altogether, our results strongly support excessive Ca2+ levels as primarily responsible for the observed activation of asp/glu exchange rates, whereas genetic contributions appear neither widespread nor necessary, at least in our postmortem and genetic samples.

Our results point toward the possible existence of a protective SLC25A12 gene variant in a sizable group of unaffected siblings. This cannot be conclusively demonstrated with our sample size of 104 families including one or more unaffected sibling.

On the other hand, our results would provide further support for key contributions of Ca2+-triggered AGC1 activity to autism pathogenesis. Increased asp/glu exchange rates provide more reducing equivalents (that is, NADH) to the respiratory chain and could foster oxidative stress,24 which was previously found increased measuring peripheral markers in autism.55 Also overexpression of AGC1 in cell culture has been recently found associated with a biphasic response, characterized initially by enhanced neurite outgrowth, which subsequently slows down and ends in early cell death.56 This response is seemingly compatible with an initial overproduction of ATP paralleled by a progressive build up of oxidative stress leading to cell damage. Oxidative stress, in addition to lipid and protein oxidation,55 can also produce genomic instability and stimulate cell cycle progression, pathophysiological events likely to be important in autism pathogenesis9,57,58 In this regard, the interindividual variability in oxidative damage reported in our study is not at all surprising, as the balance between ROS production and antioxidant agents leaves ample room for genetic and environmental influences

The present results can potentially pave the path to targeted preventive and therapeutic strategies. One important example is represented by thimerosal, an ethyl-mercury compound used as a preservative in vaccines.59,60 Thimerosal has drawn attention following initial anecdotal reports by some parents linking vaccinations to behavioral regression and to the onset of autism in their child within a matter of days or few weeks. Thimerosal is a Ca2+-mobilizing agent, capable of releasing Ca2+ from intracellular stores and increasing Ca2+ entry.61 Despite its short half-life compared to inorganic mercury, it undergoes preferential accumulation in the CNS, affecting the microglia and producing strain-dependent neurotoxic effects in rodents.62,63 This strain dependency, in conjunction with the present data, suggests that thimerosal could contribute to produce an unbalanced Ca2+ homeostasis in genetically vulnerable individuals. Indeed, a postnatal exposure to thimerosal is not reconcilable with the prenatal onset of neurodevelopmental anomalies leading to autism.

Also large retrospective epidemiological studies confirm that thimerosal neither causes autism, nor provides large-scale contributions to its pathogenesis. 2,60 However, our results suggest that thimerosal could conceivably precipitate an abrupt onset in a subset of children who would have otherwise developed autistic symptoms more insidiously. At the same time, we cannot exclude that thimerosal and other Ca2+-mobilizing environmental factors could also push genetically vulnerable individuals along the autism-spectrum toward more severe forms of the disease. On the basis of the present study, the elimination of thimerosal from vaccines, undertaken in the United States and Canada, is a well-justified safety measure.

Pharmacological treatments able to modulate extracellular Ca2+ entry, intracellular Ca2+ release from the endoplasmic reticulum or putative upstream immune mechanisms affecting either or both the pathways are, at least in principle, already available. However, caution should be exercised in translating the present findings into therapeutic interventions prior to at least one replication in an independent cohort of brain samples and to assessments of Ca2+ homeostasis in vivo. In particular, our findings in no way support the use of Ca2+ chelation as a therapeutic approach in autism. Ca2+ chelation has not only been purported of benefit in few anecdotal reports and small-sized open trials, but also carries a substantial risk to produce hypocalcemia, resulting in recent deaths of autistic children.64,65 Pharmacologically reducing Ca2+ entry into cells or blunting the oxidative damage produced by AGC activation seemingly represent more amenable and less dangerous therapeutic strategies. It is nonetheless difficult to predict the actual efficacy of treatments initiated during childhood on pathogenetic mechanisms active since early prenatal development. In this regard, the identification and functional characterization of protective SLC25A12 gene variants, if existent, could provide additional critical information on the contribution of AGC activation and oxidative stress to autism pathogenesis.



Solute carrier family 1 (glial high-affinity glutamate transporter), member 3, also known as SLC1A3, is a protein that, in humans, is encoded by the SLC1A3 gene.[5] SLC1A3 is also often called the GLutamate ASpartate Transporter (GLAST) or Amino Acid Transporter 1 (EAAT1) Excitatory.

GLAST is predominantly expressed in the plasma membrane, allowing it to remove glutamate from the extracellular space.[6] It has also been localized in the inner mitochondrial membrane as part of the malate-aspartate shuttle.[7]



VERY thorough but rather complex

N-Acetylaspartate (NAA) is employed as a non-invasive marker for neuronal health using proton magnetic resonance spectroscopy (MRS). This utility is afforded by the fact that NAA is one of the most concentrated brain metabolites and that it produces the largest peak in MRS scans of the healthy human brain. NAA levels in the brain are reduced proportionately to the degree of tissue damage after traumatic brain injury (TBI) and the reductions parallel the reductions in ATP levels. Because NAA is the most concentrated acetylated metabolite in the brain, we have hypothesized that NAA acts in part as an extensive reservoir of acetate for acetyl coenzyme A synthesis. Therefore, the loss of NAA after TBI impairs acetyl coenzyme A dependent functions including energy derivation, lipid synthesis, and protein acetylation reactions in distinct ways in different cell populations. The enzymes involved in synthesizing and metabolizing NAA are predominantly expressed in neurons and oligodendrocytes, respectively, and therefore some proportion of NAA must be transferred between cell types before the acetate can be liberated, converted to acetyl coenzyme A and utilized. Studies have indicated that glucose metabolism in neurons is reduced, but that acetate metabolism in astrocytes is increased following TBI, possibly reflecting an increased role for non-glucose energy sources in response to injury. NAA can provide additional acetate for intercellular metabolite trafficking to maintain acetyl CoA levels after injury. Here we explore changes in NAA, acetate, and acetyl coenzyme A metabolism in response to brain injury.
N-acetylaspartate (NAA) is one of the most abundant brain metabolites and is highly concentrated in neurons, but it remains to be determined why neurons synthesize so much of this particular acetylated amino acid. Early research implicated NAA in lipid synthesis in the brain, especially during postnatal myelination.
Subsequently it was discovered that mutations in the gene for the enzyme that deacetylates NAA, known as aspartoacylase or ASPA, lead to the fatal neurodegenerative disorder known as Canavan disease.
One line of research has focused on the lack of catabolism leading to a toxic buildup of NAA in the brain as the primary etiological component. Another line of research has suggested that the lack of catabolism results in an acetate deficiency in oligodendrocytes during brain development that subsequently limits acetyl coenzyme A (acetyl CoA) availability during this critical period of myelination. There is experimental support for both mechanisms, and it is possible that both are operative.
The loss of NAA after TBI is paralleled by a loss of ATP, acetyl CoA, and other metabolites associated with energy metabolism (Vagnozzi et al., 2007) indicating a substantial impact on neuroenergetics. The connections between NAA and brain energy metabolism are not entirely clear
NAA is synthesized from acetyl CoA and aspartate, and because of the exceptionally high concentration in the human brain (~10 mM) some proportion of acetyl CoA must be utilized to maintain NAA levels, and that proportion may change with brain injury. Signoretti and colleagues have shown that severe brain injury results in a very rapid drop in NAA levels that is paralleled by a similar reduction in ATP levels, suggesting that NAA is utilized rapidly in response to injury

NAA Synthesis and the Mitochondrial Malate-Aspartate Shuttle

The malate-aspartate shuttle functions to move reducing equivalents into the mitochondrial matrix in the form of malate, whereas the major mitochondrial output through this complex is aspartate. Specifically, aralar1 moves cytoplasmic glutamate into mitochondria, while moving mitochondrially synthesized aspartate out. Without aralar1, brain mitochondrial glutamate import and aspartate export are crippled.

The connection between a lack of aralar1 expression and dramatically reduced NAA synthesis has at least two potential explanations. First, as suggested by Jalil et al. (2005) it could be due to the lack of mitochondrial aspartate output, which in turn would limit substrate availability for microsomal Asp-NAT to synthesize NAA. The other possible explanation is that the lack of glutamate uptake into neuronal mitochondria prevents intramitochondrial aspartate synthesis via the aspartate aminotransferase reaction which converts glutamate and oxaloacetate into α-ketoglutarate and aspartate. In this case the lack of intramitochondrial aspartate synthesis would be the limiting factor in NAA synthesis, leading to decreases in NAA levels. It is also possible that both of these mechanisms are responsible for the large drop in NAA levels observed in aralar1-deficient mice. One of the more interesting outcomes of aralar1 deficiency in addition to the large decrease in brain NAA levels is hypomyelination


NAA and Lipid Synthesis 


Neurons provide key metabolites to their ensheathing oligodendrocytes for the purposes of myelination, myelin maintenance, and myelin sheath repair, including choline, palmitate, acetate, phosphate, and ethanolamine (Ledeen, 1984). NAA is among the trophic neuronally derived metabolites that are transferred to oligodendrocytes for use in myelination and myelin repair.

The synthesis of NAA requires the utilization of existing acetyl CoA and therefore NAA synthesis consumes a portion of brain acetyl CoA stores. Therefore NAA may be acting as a storage and transport form of acetate in the CNS that can be used for subsequent de novo synthesis of acetyl CoA, especially in oligodendrocytes


Inhibit AGC1?


The mitochondrial aspartate-glutamate carrier isoform 1 (AGC1) catalyzes a Ca2+-stimulated export of aspartate to the cytosol in exchange for glutamate, and is a key component of the malate-aspartate shuttle which transfers NADH reducing equivalents from the cytosol to mitochondria. By sustaining the complete glucose oxidation, AGC1 is thought to be important in providing energy for cells, in particular in the CNS and muscle where this protein is mainly expressed. Defects in the AGC1 gene cause AGC1 deficiency, an infantile encephalopathy with delayed myelination and reduced brain N-acetylaspartate (NAA) levels, the precursor of myelin synthesis in the CNS. Here, we show that undifferentiated Neuro2A cells with down-regulated AGC1 display a significant proliferation deficit associated with reduced mitochondrial respiration, and are unable to synthesize NAA properly. In the presence of high glutamine oxidation, cells with reduced AGC1 restore cell proliferation, although oxidative stress increases and NAA synthesis deficit persists. Our data suggest that the cellular energetic deficit due to AGC1 impairment is associated with inappropriate aspartate levels to support neuronal proliferation when glutamine is not used as metabolic substrate, and we propose that delayed myelination in AGC1 deficiency patients could be attributable, at least in part, to neuronal loss combined with lack of NAA synthesis occurring during the nervous system development.




Abstract

Ca2+ signaling in mitochondria is important to tune mitochondrial function to a variety of extracellular stimuli. The main mechanism is Ca2+ entry in mitochondria via the Ca2+ uniporter followed by Ca2+ activation of three dehydrogenases in the mitochondrial matrix. This results in increases in mitochondrial NADH/NAD ratios and ATP levels and increased substrate uptake by mitochondria. We review evidence gathered more than 20 years ago and recent work indicating that substrate uptake, mitochondrial NADH/NAD ratios, and ATP levels may be also activated in response to cytosolic Ca2+ signals via a mechanism that does not require the entry of Ca2+ in mitochondria, a mechanism depending on the activity of Ca2+-dependent mitochondrial carriers (CaMC). CaMCs fall into two groups, the aspartate-glutamate carriers (AGC) and the ATP-Mg/Pi carriers, also named SCaMC (for short CaMC). The two mammalian AGCs, aralar and citrin, are members of the malate-aspartate NADH shuttle, and citrin, the liver AGC, is also a member of the urea cycle. Both types of CaMCs are activated by Ca2+ in the intermembrane space and function together with the Ca2+ uniporter in decoding the Ca2+ signal into a mitochondrial response.


www.uniprot.org/uniprot/Q12482
Calcium-dependent mitochondrial aspartate and glutamate carrier. Transport of glutamate in mitochondria is required for mitochondrial transamination reactions and ornithine synthesis. Plays also a role in malate-aspartate NADH shuttle, which is critical for growth on acetate and fatty acids.

The aspartate/glutamate carrier isoform 1 is an essential mitochondrial transporter that exchanges intramitochondrial aspartate and cytosolic glutamate across the inner mitochondrial membrane. It is expressed in brain, heart and muscle and is involved in important biological processes, including myelination. However, the signals that regulate the expression of this transporter are still largely unknown. In this study we first identify a CREB binding site within the aspartate/glutamate carrier gene promoter that acts as a strong enhancer element in neuronal SH-SY5Y cells. This element is regulated by active, phosphorylated CREB protein and by signal pathways that modify the activity of CREB itself and, most noticeably, by intracellular Ca2+ levels. Specifically, aspartate/glutamate carrier gene expression is induced via CREB by forskolin while it is inhibited by the PKA inhibitor, H89. Furthermore, the CREB-induced activation of gene expression is increased by thapsigargin, which enhances cytosolic Ca2+, while it is inhibited by BAPTA-AM that reduces cytosolic Ca2+ or by STO-609, which inhibits CaMK-IV phosphorylation. We further show that CREB-dependent regulation of aspartate/glutamate carrier gene expression occurs in neuronal cells in response to pathological (inflammation) and physiological (differentiation) conditions. Since this carrier is necessary for neuronal functions and is involved in myelinogenesis, our results highlight that targeting of CREB activity and Ca2+ might be therapeutically exploited to increase aspartate/glutamate carrier gene expression in neurodegenerative diseases.

Studies in animal models have highlighted the relevance of AGC1 in the physiology of neurons. AGC1 knockout mice showed a dramatic drop in brain aspartate levels, with a concomitant reduction in N-acetylaspartate (NAA) synthesis and hypomyelination (Jalil et al., 2005). The connection between lack of AGC1 and drop in NAA synthesis may due to the lack of mitochondrial aspartate output, which in turn would limit availability of NAA-derived acetate needed for lipid biosynthesis resulting in hypomyelination. Numerous studies have indeed demonstrated that acetate moieties of NAA are incorporated into brain lipids during the development of the central nervous system, hence strongly suggesting that AGC1 may be crucially involved in the myelination). In support of this conclusion, children harboring mutations of the SLC25A12 gene display severe developmental delay, epilepsy, hypotonia hallmarked by hypomyelination and decreased NAA in the brain (Wibom et al., 2009; Falk et al., 2014). The chromosomal region containing the gene encoding AGC1 has also been identified as a putative autism susceptibility locus (Ramoz et al., 2004; Turunen et al., 2008; Palmieri et al., 2010). In addition, interest in the involvement of mitochondria in neurodegenerative and neuroinflammamtory disorders, such as Parkinson's and Alzheimer's disease, and multiple sclerosis is emerging (Lin and Beal, 2006)

Despite the well-established role of NAA in myelin biosynthesis, it is still unknown in which subcellular compartment the biosynthesis occurs. Different studies have provided evidence that the aspartate-N-acetyltransferase (Asp-NAT), the enzyme that catalyzes the biosynthesis of NAA, is localized in the mitochondria (Patel and Clark, 1979; Madhavarao et al., 2003; Arun et al., 2009). However, other studies performed in primary neuronal cultures established that Asp-NAT is located in the endoplasmic reticulum as well (Wiame et al., 2009; Tahay et al., 2012). A colocalization was reported by other authors (Lu et al., 2004; Ariyannur et al., 2010).

3.1. AGC1 expression is downregulated by inflammatory cytokines

3.3. The decrease in AGC1 expression in neuroinflammation is most likely caused by the downregulation of CREB

3.4. Cytosolic Ca2+ level affects AGC1 gene expression via CREB
Because Ca2+ is a well-known CREB inducer (Sheng and Greenberg, 1990) and is also known to stimulate AGC1 activity (Palmieri et al., 2001; Lasorsa et al., 2003; Contreras et al., 2007), we investigated whether alterations in the pool of intracellular Ca2 affect AGC1 gene expression. 

Glutamate is the only amino acid extracted by healthy myocardium in net amounts, with uptake further increased during hypoxic or ischemic conditions. Glutamate supplementation provides cardioprotection from hypoxic and reperfusion injury through several metabolic pathways that depend upon adequate transport of glutamate into the mitochondria. Glutamate transport across the inner mitochondrial membrane is a key component of the malate/aspartate shuttle. Glutamate transport in the brain has been well characterized since the discovery of the excitatory amino acid transporter (EAAT) family. 


Increased expression of the glutamate transporters EAAT1 and EAAT2 in the cerebellum of post-mortem tissue from autism patients has also been reported. Because EAAT expression is controlled in part by the extracellular concentration of glutamate, it is possible that the EAAT overexpression is due to the increased glutamate concentration seen in plasma and spectroscopic studies, as reviewed above.







Fig. 2 The malate – aspartate shuttle (MAS) and A TP generation. MAS is the main pathway for the transfer of reducing equivalents in the form of NADH from the cytosol into the mitochondria. Cytoplasmic malate dehydrogenase reduces oxaloacetate to malate while oxidizing 


A reminder of what belongs where in a cell:-




Components of a typical animal cell:

1.      Nucleolus

2.      Nucleus

3.      Ribosome (little dots)

4.      Vesicle


6.      Golgi apparatus (or "Golgi body")

7.      Cytoskeleton

  1. Smooth endoplasmic reticulum 

9.      Mitochondrion

10.  Vacuole

11.  Cytosol (fluid that contains organelles, comprising the cytoplasm)

12.  Lysosome

13.  Centrosome




Conclusion

I hope some people made it to the end of this post. Since it was written on two computers, there may be some duplication.

It appears that most people with autism would benefit from less calcium in their brains, but this is more complex than it sounds. We need to block voltage gated calcium channels that are open, when they should be closed. We need to reduce IP3 to keep calcium locked up in the endoplasmic reticulum.

If we cannot reduce the level of Ca2+, we need to look at CREB which is mediating much of the damage. We can modify CREB via drugs that increase or decrease PKA. The only problem here is that for most people that would mean decreasing PKA, but PKA also does some other good things. At least in Alzheimer’s things do not conflict you want more CREB and more PKA.

The amino acid transporters AGC1, EAAT1 and EAAT2 are likely over activated in much autism. So we should expect lots of problems with glutamate, aspartate and indeed mitochondrial function. 

It looks like most young people with autism would benefit from more NAA. One study showed that the omega 3 oil EPA can increase NAA.  At least that is simple.

More NAA may well help correct impaired myelination.

Ideas that may potentially help in some cases of autism:-

·        L-aspartic acid / L-aspartate

·        High EPA fish oil to increase NAA

·        PDE4 inhibitors (Ibudilast or Daxas)

·        PKA inhibitors (not easy)

·        IP3R blocker (only caffeine seems currently viable and is suboptimal)

         Interactions of antagonists with subtypes of inositol 1,4,5-trisphosphate   (IP3) receptor

·        Verapamil in those with over-active (open) L-type calcium channels 



Does oral L-aspartic acid actually reach the brain? Just try some. It tastes odd, like a homemade sweet/sour flavoring gone wrong and does not dissolve in water.  It should be harmless in moderation.







73 comments:

  1. I have tried oxiracetam myself and I can confirm it has potential, for me personally it seems to help motivate me and helps against my lack of interests (it literally broadens my degree of 'liking').
    I can see how N-AA levels could indeed be linked to creativity.

    I believe I have posted this study before, but I will do it incase Tyler has not read it:

    (S)-Oxiracetam is the Active Ingredient in Oxiracetam that Alleviates the Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577264/


    @Peter, from what I understand L-aspartic acid is not that active in the brain it is mainly D-aspartic acid. However supplementing D-aspartic acid (as I have done myself and yes it did increase my emotional 'range') correlated with sleeping issues for me. ZMA (zinc magnesium aspartate) gave me sleep issues aswell, I would dream like mad on it, but the sleep quality I was getting was so poor and I would literally wake up 8-10 times per night.
    I never figured out why untill recently:

    D-aspartate modulates melatonin synthesis in rat pinealocytes.
    https://www.ncbi.nlm.nih.gov/pubmed/9682837/

    "It has been known that pinealocytes contain the highest level of D-aspartate among various neuroendocrine cells in the rat. Here, we report that exogenous D-aspartate strongly inhibited norepinephrine-dependent melatonin synthesis in the rat pineal gland, the concentration required for 50% inhibition being 75 microM. This inhibition was due at least partly to decreased norepinephrine-dependent serotonin N-acetyltransferase activity. Upon incubation, D-aspartate was gradually released from pinealocytes and accumulated in the incubation medium as determined by high-performance liquid chromatography on a Pirkle-type chiral column. These results suggest that D-aspartate acts as a negative regulator for melatonin synthesis in the pineal gland."

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    1. Aspie, the effects of L-aspartate and D-aspartate do seem to differ, but my reading of the literature suggests that it is L-aspartate that would be the relevant one. Let's see Tyler's views.

      Body builders are taking D-aspartate to increase testosterone, but a recent study showed that it actually had the opposite effect.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384294/

      Delete
    2. Im aware that they are different Peter, however l-aspartic acid can also convert into D-AA.
      This does however see a more sensible approach by letting the body decide how much L-aspartic acid gets converted into D-aspartic acid.

      However... keep in mind, alot of people (yourself included?) have said that sodium benzoate (aka cinnamon) helps lots of kids, this works by inhibiting the breakdown of D-amino aicds, this would increase D-AA in the brain.

      Im sure your aware rispderdal also does this (used both in autism and shizophrenia which clearly both have a link with NMDA).

      The effect of risperidone on D-amino acid oxidase activity as a hypothesis for a novel mechanism of action in the treatment of schizophrenia.
      https://www.ncbi.nlm.nih.gov/pubmed/19329549

      Evaluation of human D-amino acid oxidase inhibition by anti-psychotic drugs in vitro.
      https://www.ncbi.nlm.nih.gov/pubmed/25030849

      Back to racetams... they are very much underappreciated:

      A double-blind placebo controlled trial of piracetam added to risperidone in patients with autistic disorder.
      https://www.ncbi.nlm.nih.gov/pubmed/17929164

      "A significant difference was observed on the change in scores in the ABC-C Rating Scale in week 10 compared with baseline in the two groups (t = 6.017, d.f. = 38, P < 0.0001). The results suggest that a combination of atypical antipsychotic medications and a glutamate agent such as piracetam, might have increase synergistic effects in the treatment of autism."

      P<0.0001 for the rispderdal + piracetam group vs risperdal + placebo group.

      Now piracetam has many modes of action, but the main one seems that it acts upon mitochondrial membrane potential.

      Now lets look at the safety of piracetam, I'll give you an example:

      Piracetam in the treatment of cortical myoclonus.
      https://www.ncbi.nlm.nih.gov/pubmed/10338109

      "The authors present their experience of 12 patients with progressive myoclonus epilepsy in whom the administration of up to 45 g piracetam daily, when added to existing anti-epileptic treatment, caused marked and sometimes spectacular improvement and was without significant adverse effects. Improvement was maintained for up to 7 years. The use of piracetam for disabling cortical myoclonus of any etiology, either as an addition to existing antimyoclonic drugs or as monotherapy, may bring about profound improvement in disability and quality of life. Piracetam should be considered a first-line drug for the treatment of cortical myoclonus."

      So 7 years of use, sometimes life changing effects and doses up to 45 gram per day!! confirming the excellent savety profile of piracetam.

      Admittedly I do notice on piracetam that my brain speeds up a fair bit, but I dont get irritable at all on it, if anything it decreases irritability.

      Delete
    3. D-Aspartate is at very low levels in the body and brain. The vast majority of aspartate is used for the urea cycle which is one reason L-Ornithine and L-Aspartate (LOLA) is sometimes used to help deal with detoxification issues from a failing liver:

      https://www.ncbi.nlm.nih.gov/pubmed/20642112

      As for L-Aspartic Acid supplementation increasing D-Aspartic levels, I assume somebody has done a study on that. Usually increasing the L racemer form of an amino acid in the blood will increase the D form as well, but not always as the conversion from L form to D form is rate limited by enzymes.

      Delete
  2. L-Aspartic Acid supposedly will dissolve in water, but you need quite a lot of water. I think I remember that you need like 2 liters of water to dissolve a teaspoon of L-Aspartic Acid. I am pretty sure I am wrong on these measurements, just I determined it was impractical at the time. Another thing you can do is boil some water (or at least get relatively hot water) and mix L-Aspartic Acid with baking soda to yield monosodium aspartate that dissolves into water and which has a more salty taste.

    If you have a thick medium such as a smoothie, you can just add the L-Aspartic Acid directly. Also, I have used it myself chronically (for testing purposes) and it does seem to promote a sort of anhedonic response which suggests a lower mu-opioid or dopaminergic tone which is desirable in my son's case if not taken too far. Anhedonia is also linked with high glutamate levels so its mechanism of action could be via reducing glutamate levels as well (the original reason for me investigating Aspartic Acid).

    So if you are going to trial L-Aspartic Acid, this is one of those situations where you are going to want to start out small and patiently move on up in dosage till you get the right amount because even though depressing excessive glutamatergic, opioid and dopaminergic activity is generally desirable in autism, you don't want to overdo it.

    On top of that, I don't know exactly how it helps because no researcher has bothered to investigate this type of therapy as it relates to autism (the research that inspired its use was for treating opioid abstinence symptoms from a 3+ decade old study in Turkey), so it is just one of those therapies that you just have to find out for yourself and methodically test out increasing doses to see which dose helps the best or if the therapy has an undesired response or other side-effects.

    With respect to my son, it made a big immediate difference with SIB and attention around three to four years ago when I first employed this therapy to the point his teachers really noticed (they were unaware of the therapy of course). Of course this is all sample size N=1 here, but unless someone does independent research on the matter, you will just have to try it out for your child, yourself, or both.

    ReplyDelete
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    1. Ehmmmmmmm

      "I have used it myself chronically (for testing purposes) and it does seem to promote a sort of anhedonic response which suggests a lower mu-opioid or dopaminergic tone which is desirable in my son's case if not taken too far. Anhedonia is also linked with high glutamate levels so its mechanism of action could be via reducing glutamate levels as well (the original reason for me investigating Aspartic Acid)."

      This is why im wary with other people their claims, on one hand you say it promoted an anhedonic response and that this is linked with high glutamate levels, then you go on saying its mechanism of action could be through reducing glutamate. Look man... aspartic acid is as pro-glutamate as it gets, not sure if you made typos or anything but what you said there doesnt make any sense at all.

      Delete
    2. Aspie,

      Today you are the demolition man!!!
      Yes, I also thought it confusing but assumed its a typo.

      Anything pro glutamate, a no no for my son. And yes, my son has a strong built with heavy bones but I thougt he had high testosterone levels too. Now, you are saying its driven by estrogen. Again, a little confusing....do you imply that males with estrogen dominance will have broad heavy bones?

      Delete
    3. First off, I test whatever I give my children on myself first, hence my anecdotal explanation which is just my experience, not something to be taken as any sort of hard proof for my arguments.

      Secondly, anhedonia can mean many things with respect to depression. To date, there is no reliable bullet-proof method of fixing depression, likely because there can be many different biological causes just like with autism. Alsom many depression symptoms could be considered the inverse of those with low-functioning autism (low dopamine, low serotonin, etc.). High-functioning aspies or autistics like yourself can of course be very depressed, but generally don't have the same symptoms of many people with autism who also have intellectual disability (such as my son). There are many studies looking at these differences which I am sure you are aware of.

      Third, what I said about glutamate was not a typo, but I provided no context which is just as bad so I apologize. To clarify, Aspartic acid is not pro-glutamate any more than GABA is because I am not sure you understand how Glutamate/Glutamine/GABA/and Aspartate are recycled in the brain. This is why some people go crazy about MSG (Monosodium Glutamate) because they think it goes straight to their brain, when in fact it does not. Glutamate and Aspartate can enter the blood-brain barrier, but at very small amounts and they both compete with each other for access so more aspartate will compete with glutamate and aspartate though an excitatory amino acid does not bind to NMDA receptors nearly as strongly as glutamate does. For your information, the vast source of glutamate in the brain comes indirectly from glutamine which crosses the BBB much more readily.

      Hope that helps.

      Delete
    4. Aspie, here is another study which might explain the relationship of the E/I balance in the brain with respect to Glutamine. This study primarily discusses paradoxical findings with regards to an inhibitory challenge from the drug riluzole (in the discussion section, the "GABA switch" from excitatory to inhibitory function is mentioned). In particular, read about the "inhibitory index" and you may understand a little better why the E/I balance in the brain is not as simple as blood ratios of various amino acids.

      https://www.nature.com/articles/tp2017104

      Delete
    5. Tyler, do i understand your comments here right as in
      "Oral administration of aspartic acid will replace glutamate in the brain with less excitation as a consequence"?

      /Ling

      Delete
  3. Hi Peter,

    Just a note to say that this was a terrific post! I always appreciate your ability to draw valuable conclusions by seeing the big picture (i.e. connecting the dots between various lines of research).

    For example, I've been giving my daughter a fish oil high in DHA, as I assumed that DHA was the more relevant part for ASD. Now I'm going to look to provide EPA as well.

    Thanks Peter!

    AJ

    ReplyDelete
    Replies
    1. AJ, it looks like Prof Puri is a smart guy. If you read what he says, all you want is EPA and that if you add DHA you will lose the benefit of EPA. He has written a lot about the subject. His VegEPA is one of the less expensive products.

      Just google "EPA professor Puri".

      Almost all pills have both EPA and DHA, but a very small number have no DHA.

      A long time ago I tried a combined EPA/DHA pill and saw no benefit.

      I will get some VegEPA from the UK and do a two month trial. On the UK Amazon it will cost 20 pounds or $36 Canadian.

      Delete
    2. AJ, I have no idea if VegEPA is better, but it is the one from the trial and is sold on the US Amazon.

      Delete
    3. While its true that EPA and DHA are somewhat antagonistic and that an optimal ratio between the 2 is crucial ('optimal' will be different for every individual).

      Also with regards to this certain 'doctor', there are too many proclaimed doctors out there selling products.
      People need to wake up, its all about money, better off getting information from pubmed (in particular research that is not payed for by the industry trying to sell it).

      Delete
    4. Aspie, he is a Professor of Medicine at one of the UK's top Universities. He has published numerous books and papers. He has measured the change in NAA in a trial using children taking this supplement.

      http://www.imperial.ac.uk/people/basant.puri

      Delete
    5. Hi Peter,

      Thanks so much for providing the additional info about both the product, and that DHA may in fact inhibit the benefit EPA for ASD.

      I will definitely trial the EPA only and put the DHA on hold while I do the trial.

      Thanks very much again Peter!

      AJ

      Delete
  4. AJ, I had the OmegaVia site bookmarked to try their product when we finished our Nordic Naturals ProEPA supply. OV does have an EPA only product. The NN has DHA, a smaller ratio, in spite of it, I do see obvious improvement in my son on higher epa. Looking forward to seeing how much more improvement with just EPA! You might want to check OV website - I think it might cost a little less? Seems their quality is good too
    https://shop.omegavia.com/products/omegavia-epa-500?variant=14633097351
    Thanks again to Peter for providing such a nice service to families by generously sharing his research.

    ReplyDelete
    Replies
    1. Hi Tanya,

      Thanks very much for providing this option! I'm going to check it out to see which option works best for us (i.e. cost and shipping).

      By the way, I just also ordered a Rice Bran Extract (RBE)supplement based on the following:

      https://www.ncbi.nlm.nih.gov/pubmed/23827162

      Interestingly enough, my daughter scored low on Citrate Synthase and Complex I in Dr. G's mito test, and RBE seems to help with both, so between switching from DHA to EPA and adding RBE, I'm hoping we'll get some added improvement.

      Hope all is well Tanya and Happy Easter!

      AJ

      Delete
    2. Hi Tanya,

      I just ordered the OmegaVia EPA - great suggestion! :)

      It was the best value when I compared it to the others.

      Thanks Tanya and fingers crossed.

      AJ

      Delete
    3. OmegaVia EPA is ethyl esters according to the manufacturer. There are studies claiming that absorption of ethyl esters is worse that triglycerides https://www.intelligentlabs.org/whats-the-difference-between-triglyceride-and-ethyl-ester-omega-3-fish-oil/

      Nordic's EPA XTRA has more than 3x of EPA than DHA and is triglyceride-based oil. In the end, for all practical purposes, you won't see much difference between Oemegavia or any other EPA-rich oil.

      Delete
    4. Hi Anon, this is actually very good information. Of course, it would have been even more helpful if you had told me just before I bought two bottles of OmegaVia ;)

      I assumed EPA was EPA, so this is actually really good to know as I would have always looked for high quality EPA without regard to Ethyl Ester versus triglyceride.

      I will switch to the PharmEPA thanks to your info, and again appreciate the insight!

      AJ

      Delete
    5. AJ, I also concluded PharmEPA is the most potent. If you read the user comments, a lot of people find it useful. It is from the same company as VegEPA, and they say if you need a lot of EPA, as in ME/CFS, it is the best choice.

      Delete
    6. AJ, and then hmmmm: This is from OV’s site on the question:
      https://omegavia.com/fish-oil-ethyl-ester-vs-triglyceride-revisited/
      Well, I have already placed my order and will give it a try anyway. But it looks like according to their site, you can get your money back if not satisfied.

      Delete
    7. AJ, I just read through the comments from the page I sent and apparently they’ve switched to TG form due to customer demand and not from “compelling science”. Lord have mercy - sigh - all of this “controversy” reminds me of our early biomed days on the yahoo health groups (long before Facebook ha!) with parents bickering over what supplement is right and wrong or being no sycophantic over their chelation guru.. It will always be conflicting. Sigh. Anyway, best of wishes for whichever product you use! And happy Easter to you as well.

      Delete
    8. Hi Tanya,

      Hope all is well!

      Who would have thought a few days ago we would have dueling forms of EPA we would be scrutinizing? :)

      I did just order PharmEPA last night, and what I think I will do is use one in the AM and one in the PM, so that I try both and then likely just stick to PharmEPA once they're both done. But its good to know that OV switched to TG so that either one is better absorbed.

      I'm keeping my fingers crossed that either one will have a positive impact, and I'm excited that we've found another avenue to help our kids.

      Hope you have a wonderful day Tanya, and thanks for the additional info!

      AJ

      Delete
    9. Hi Peter,

      Thanks again for providing this great information! I am really looking forward to trying EPA. I feel like my daughter is right on the precipice of great things if I can just make a little bit more of an improvement (especially on the cognitive side).

      By the way, I don't know if you saw one of my posts, but I found that Rice Bran Extract may help increase Citrate Synthase and Complex I in the mitochondria, and these are two areas my daughter was low. I just started this last night, so will track any improvement over the next couple of months.

      Thanks again very much for the info on EPA, I'm optimistic about it.

      AJ

      Delete
    10. AJ, did you find PharmEPA in North America?? I thought it only shipped from UK? Unfortunately, my order from Bimuno UK I still haven’t received - hope it is not lost or stuck in customs thanks to all the craziness happening in my country now ha!

      Delete
    11. Hi Tanya,

      I did find it on Amazon, and there are 3 buying options on the US site (I bought off the Canadian Amazon site):

      https://www.amazon.com/Pharmepa-Strength-Pharmaceutical-grade-Absorption-function/dp/B007TUK2IE/ref=sr_1_1_a_it?ie=UTF8&qid=1522793271&sr=8-1&keywords=PharmEPA

      And oh yes, it takes a while to get Bimuno and once it arrives, it sometimes looks like something out of Indiana Jones (i.e. it shows that it had a long journey :)

      The good news is that we've been using it for about a year, no issues at all with continued use. I use one packet a day (at night in my daughter's Almond Milk).

      I don't know how much it has played a role in my daughter's improvement, but I keep using it just in case.

      They do sometimes have sales too, so I keep an eye open on their site so that I can get it when its on sale.

      Have a great day Tanya!

      AJ

      Delete
    12. Oh wow AJ I didn’t know you were using bimuno - it’s nice to hear a good report from someone I *know* ;)

      Delete
  5. Here is some novel research which I thought might be another major avenue of exploration as it relates to autism and synaptic inhibitory function:

    Press Release:

    https://www.sciencedaily.com/releases/2018/03/180326090559.htm

    What the researchers showed here is that in the process of refilling synaptic vesicles with neurotransmityres for distribution across a synapse, the rate of refilling takes much longer for GABA than glutamate and that this duration was longer than endocytosis which has long been assumed to be the rate limiting step for vesicle formation. It was also found that the time it takes for a GABA vesicle to be refilled was the same as that of synaptic depression for GABA synapses (recovery time).

    So with regards to GABA if there is some hiccup in the refilling process, then you can expect the rate of synaptic depression to be longer which means GABA synapses will be less effective at signalling and fire less often. Parvalbumin inhibitory interneurons which don't seem to work properly in autism seem to be what causes reduced gamma rhythms in autism and properly timed gamma rhythms are essential for the proper gating of sensory information.

    Beyond what the press releasr and study describes, these are just my observations, though if I was a researcher studying "autism and GABA synapses", this new information would look like very low-hanging fruit to pick at.

    ReplyDelete
  6. Hi Peter,yesterday I ordered omegaVia, thanks Tanya for the info,I was in higher Epa since 4 months with good results.Couldn´t find sarcosine available, would be ok if I do another trial with L Serine?I was giving half a teaspoon,a very low amount.Which would be the best dose in mg? Valentina

    ReplyDelete
    Replies
    1. Valentina, in this schizophrenia study using D-serine they found a dose of at least 60 mg/kg/day was needed.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3111070/

      Delete
    2. Ok, i don't know why d serine is not regarded as safe by FDA in spite of the research.I have l serine, wich is not so well metabolized. Valentina

      Delete
    3. Hi Valentina,

      I had looked for Sarcosine a little while ago and bookmarked the following for if / when I would decide to give it a shot:

      https://www.powdercity.com/products/sarcosine

      If you do try it, please share how it worked.

      Hope this helps Valentina!

      AJ

      Delete
    4. Hi AJ,thanks!I was looking at powdercity.com,it seems that is the only place to find Sarcosine at the moment and so cheap.I will try it and tell you how it worked,think it´s better to give it in separated daily doses.Sure I will tell you how it worked.Good lack with your EPA trial !
      Valentina

      Delete
    5. Hi Valentina,

      My pleasure! I hope it helps.

      And thanks for the well wishes on EPA. I'm hoping it will provide some benefits.

      Have a wonderful night Valentina!

      AJ

      Delete
    6. AJ and Tanya, I looked back on my order of Omegavia,and it says:"triglyceride form EPA only fórmula". Valentina

      Delete
    7. Yes Valentina, it is. They switched apparently. Thank heavens we are “safe” haha. Best wishes with your trial.

      Delete
    8. Yes! I was sure that had read correctly when I placed the order.
      All best for you!
      Valentina

      Delete
  7. Hello everyone,

    I just wanted to share a few interesting new papers:

    1. Cytokine profile in autistic patients.

    https://www.ncbi.nlm.nih.gov/pubmed/29602155

    Quick take: "TNF-α, IL-6 and IL-17 have been shown to be significantly up-regulated in ASD patients compared with healthy subjects (P < 0.0001, P = 0.001 and P < 0.0001 respectively). IL-2 has been shown to be significantly down-regulated in total ASD patients (P < 0.0001)."

    2. Chinese children with autism: A multiple chemical elements profile in erythrocytes.

    https://www.ncbi.nlm.nih.gov/pubmed/29603680

    Quick take: " Erythrocyte levels of 11 elements (32%) among 34 detected elements in autistic group were significantly different from those in the TDC group. To our knowledge, this is the first study which compared the levels of rare earth elements in erythrocytes between children with or without ASD. Five elements including Pb, Na, Ca, Sb, and La are associated with the Childhood Autism Rating Scale (CARS) total score."

    3. CNTNAP2 stabilizes interneuron dendritic arbors through CASK

    http://www.nature.com/articles/s41380-018-0027-3

    Quick take: "...we uncovered relationships between nanoscale CNTNAP2 protein localization and dendrite arborization patterns."

    +

    "...we show that these effects are mediated at the membrane by the interaction of CNTNAP2’s C-terminus with calcium/calmodulin-dependent serine protein kinase (CASK), another ASD/ID risk gene. Finally, we show that adult Cntnap2 KO mice have reduced interneuron dendritic length and branching in particular cortical regions, as well as decreased CASK levels in the cortical membrane fraction."

    AJ

    ReplyDelete
  8. AJ, CASK interacts with TBR1 which is also an autism gene, and together they upregulate NMDARr subunit N2B and the reelin gene among other things.
    My research efforts have so far revealed that PKA phosphorylation, PDE-4 inhibitors and forskolin should be able to attenuate downregulation in these areas.

    /Ling

    ReplyDelete
  9. Hi Ling,

    Very interesting findings, both in terms of the CASK / TBR1 interaction and the PKA phosphorylation, PDE-4 inhibitors, and forskolin attenuating downregulation in the relevant areas.

    Forskolin is something that keeps popping up on my radar and I haven't yet tried it. I'll have to look more closely into what else it does. I may put it on my list of future options to try.

    Have a great day Ling!

    AJ

    ReplyDelete
    Replies
    1. Yes, forskolin has popped up several times for me too. At the moment I think there are too many possible side-effects and uncertainties about long-term use to keep me away from it.
      /Ling

      Delete
  10. Peter, Tanya,

    I feel instictively that my son needs omegas but my instinct has so far not been proven right as my son showed no benefits on cod liver oil or barleans omega swirl....on the contrary in fact. However, he has now started developing seasonal mild skin rashes, allergies due to dry skin and has attention issues, both ofofpotentially which can be potentially helped through fatty acids. Should I give Pharma EPA a try? Its available on amazon india.

    Secondly there is a product out there called Restore, consisting o f trihydritte (ancient minerals, basically carbon based) which has been publicized much as helping with gut health...is it all dubious or seems credible?
    All this seems so surreal...but after an elderly relative wa diagnosed with chronic gi infections leading to weight loss, severe anemia and all symptoms suggestive of cancer which led to multiple biopsies, gut health is becoming a real concern for us who are hypersensitive to the poison in our food, air and water.

    ReplyDelete
    Replies
    1. Kritika, I also saw no benefit from regular fish oil, but PharmaEPA seems to produce some unexpected benefits that are tangible, like changes in skin. So if spots and rashes disappear then you would have some evidence that something is changing.

      I will give it a try.

      Given the pollution in Delhi did you ever try sulforaphane?

      https://www.sciencedaily.com/releases/2014/06/140616102410.htm

      Delete
    2. Kritika, my son had the very same reaction to cod liver oil - no benefit and it caused dry skin. Maybe due to the vit A? We also saw no benefit on other omega brands we tried when he was younger. The Barleans swirl has so many other ingredients he could be reacting to - maybe even the borage oil? I would definitely try the pharmEPA. Like I mentioned before, I saw obvious almost immediate improvement just from the higher EPA to DHA ratio product we started using last fall. The gut stuff is so challenging. Try to see if you can figure out food triggers. If he is bloated, then he has them. Also try to lower other inflammatory seed oils. Avoid fried foods. It will help a lot. Does he like olive oil? I really cannot share anything on the Restore product. When it first came out a few years ago, I caved and ordered it, but never used it.

      Delete
    3. Ok, Peter, Tanya, I will trial the EPA. At least it seems relatively harmless.
      Tanya, our sons seem quite similar in their sensitivities and reactions which actually was the reason I wanted to trial EPA when you first reported good,results with it.

      Peter, I so want to try sulphoraphane but hesitate because of some side effects related to elevated liver enzymes about which I had read in some research article. Maybe small quantities is the way to go.

      There has to be something that works without backfiring. My rope has multiple knots as I have reached the end so many times. Prof Puri, you better be right about this EPA thing!

      Delete
    4. Hi Kritika,what a coincidence!a few days ago I ordered Restore, my son has chronic constipation ,I heard excellent comments about it.Lets see how it goes,I don´t know what to do with his problem,nothing seems to work!
      Valentina

      Delete
    5. Valentina,

      Do let me know about your results. My son does not have constipation, has a healthy diet, is active but still his stomach remains swollen and this has really become noticeable in the past few months. This indicates digestive issues. And though addressing those will not cure my sons autism, it will help with so many areas as he has internal hypersensitivity and indigestion affects his sleep and sensory processing. That is why I am looking forward to the chemotrypsin phase 3 trial outcome. Maybe I should retrial digestive enzymes.

      All the best....I hope things are restored on your side and do share the outcome.

      Regards

      Delete
    6. Tanya,

      There definitely is a food trigger but I do not know how to nail it down. His appetite for biscuits, chocolates and spicy crispies is an embarrassment, though I try to balance it out with fruits and vegetables.

      Tanya, since you are our resident biomedical expert, and Peter has started relenting a bit, and autismweb has closed down, I would like your opinion on digestive enzymes once again and on coconut oil as my son has developed a taste for it and scooping out and eating it straight out of the tub. Is there any harm in letting him do this?

      Thanks Tanya... your advice is always invaluable.

      Delete
    7. Dear Kritika, more like resident biomed flunkie expert ;)
      And yet another thing in common: my son would crave coconut oil almost ravenously. And yep straight from the tub using a big spoon. I ended up chalking this one up to almost like an addictive behavior - relating to dopamine issues. His behavior would be horrible too after eating it - so I stopped buying and using it. Just sticking with olive oil. How is your son after eating it? Does he act like a junkie if he doesn’t get it?
      I never had any luck with plant based enzymes. We tried creon also and I really couldn’t tell then. I wonder now if I might see benefit. I need to run an OAT. An OAT might really help shed some light in things for you - it has some useful digestion markers, like oxalates and things like fatty acid oxidation. At least the one Great Plains offers. Not sure how that would work shipping a sample from India? Also not sure of total cost because my pediatrician would always sign for it and my insurance paid for most. I wish I could tell you of a lovely magic bullet for the gut stuff. I just received my Bimuno and we are going to see how far we can get with that. My son’s gut has improved a lot, but the flares due to certain foods are still there. Gastrocrom never really helped with those certain foods. I think since I removed him from big emotional triggers, the need for mast cell stabilizers has gone down.

      Delete
    8. Tanya,

      My sons OAT came out normal....it did not test for oxalates, bacterial markers or neurotransmitter levels. He seems to have an oxalate problem though as a few times he haf pain while urinating and though an ultra sound and urine test detected nothing abnormal,.an SOS measure in the form of alkasol, did resolve the probem. I think I shared this with you.

      I was asking about coconut oil because last year after reading about its miraculous healing properties, especially the case study, which I am sure all of us know, about how a doctor reversed her husbsnds Alzheimer after administering him coconut oil, I had tried to give it to him, unsuccessfully. But now he seems to love it. No his behaviour does not deteriorate nor does he behave like an addict when refused. Probably mums angry glares do not give him room to show his true colors.

      I too had used plant based digestive enzymes but I was doing it together with other things...

      Dear AJ, certainly the world of autism spins in opposite directions at the same time...so much so, that even our Peter has started suggesting that trialling multiple interventions at the same time might not be such a bad idea..chuck the one thing at a time protocol. I am as confused as ever.

      Delete
    9. Hi Kritika,

      Hope you're doing well!

      By the way, mums angry glares do also work on husbands, and their effectiveness are therefore not only limited to children :)

      Kritika, I noticed that your OAT test didn't look for several items that are in the Great Plains Lab test. Interestingly enough, the biggest findings for us were in the Bacterial markers (which led us to attack both bad yeast and bacteria) and neurotransmitter levels (high Quinolinic / 5-HIAA Ratio).

      I know I had noted this before, but the following is the OAT sample report from GPL:

      https://static1.squarespace.com/static/560ac814e4b067a33438ecea/t/5ac3917e352f533cbdd56a5c/1522766208767/New+Oat+Sample+Report+April+2018.pdf

      I just re-ordered a follow-up OAT and it was $380 Canadian.

      As far as trialing one thing at a time, I gave up on that idea very quickly, as there were too many things to try and it would take forever to get to them.

      My daughter's behavior has recently deteriorated a bit (more fussiness, temper tantrums, etc.) and my wife asked me which of the new supplements would cause that. I explained to her that I don't know which would / could, and each kid is different and we don't even know if it was due to a new supplement. I had started her on Methioinine at about the time her behavior deteriorated a bit, so I have put that on hold.

      I truly believe that ASD is THE most complex condition I've ever heard of, and hopefully we'll have more tests available soon to allow us to determine what the causes are for each of our kids so that we can tailor treatment instead of the current trial and error.

      Have a great day Kritika!

      AJ

      Delete
    10. Hello AJ,

      So now you are the poor recipient of angry glares from two women...dear wife and daughter dear. Grin and bear.

      I will look into the parameters tested by GPL and try to find if we can get them covered under multiple tests if not under a single OAT test like that done by GPL. Getting the frozen urine sample to GPL has some issues...that's what somebody told me. As for now, I am focussing on EPA and bumetanide and fiddling with the idea of Restore.

      As for your daughter, maybe its as simple as an impending flu but last year this is what happened with my son. He was doing good on a combination and then I added something and things just went bad from there and unfortunately my son could never again tolerate even the supps he was earlier doing good on. What I mean is..it would be wise not to overdo. Again, it could just be a flu, or methionine or increased awareness.

      Thanks AJ, you are a kind person and your positivity is always uplifting.

      All the best



      Delete
    11. Hi Kritika,

      Thank you for the kinds words!

      And I know, I am in double trouble with the two ladies :)

      Actually, my wife and I were just talking about the fact that our daughter whined much less tonight than she has in many months, and her speech seemed a bit more complex.

      Our only very recent changes have been:

      1. Adding EPA (and significantly reducing DHA)
      2. Adding Rice Bran Extract - this is very specific to my daughter as Dr. G's mito test showed she was low and Citrate Synthase and Complex I, and I found RBE may help
      3. Stopping L-Methionine.

      If tonight's version of my daughter is the new version that will remain, it's a good improvement. I suspect its the combination of the above 3 changes, so I will continue them and hopefully the improved mood and even speech continue.

      So I'm back to only one source of angry glares :)

      That's a 50% reduction, I'll take it.

      I'm looking forward to hearing how your son does with EPA - hopefully really well.

      Have a great day Kritika!

      AJ

      Delete
  11. Hi everyone,

    I just saw this paper (looks more like a review but I hadn't seen the key point it made before):

    https://www.ncbi.nlm.nih.gov/pubmed/29614380

    Serotonin as a Link Between the Gut-Brain-Microbiome Axis in Autism Spectrum Disorders.

    Abstract
    Autism-spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and repetitive patterns of behavior. ASD is, however, often associated with medical comorbidities and gastrointestinal (GI) dysfunction is among the most common. Studies have demonstrated a correlation between GI dysfunction and the degree of social impairment in ASD. The etiology of GI abnormalities in ASD is unclear, though the association between GI dysfunction and ASD-associated behaviors suggest that overlapping developmental defects in the brain and the intestine and/or a defect in communication between the enteric and central nervous systems (ENS and CNS, respectively), known as the gut-brain axis, could be responsible for the observed phenotypes. Brain-gut abnormalities have been increasingly implicated in several disease processes, including ASD. As a critical modulator of ENS and CNS development and function, serotonin may be a nexus for the gut-brain axis in ASD. This paper reviews the role of serotonin in ASD from the perspective of the ENS. A murine model that has been demonstrated to possess brain, behavioral and GI abnormalities mimicking those seen in ASD harbors the most common serotonin transporter (SERT) based mutation (SERT Ala56) found in children with ASD. Discussion of the gut-brain manifestations in the SERT Ala56 mice, and their correction with developmental administration of a 5-HT4 agonist, are also addressed in conjunction with other future directions for diagnosis and treatment.


    ************************************

    I just did a quick Google search for a natural / easily accessible 5-HT4 agonist and nothing jumped out.

    I'm going to keep digging, but if anyone knows of one, would you kindly share? If I find anything, I will share as well.

    AJ

    P.S. my PharmEPA arrived today so my daughter just had her first dose.

    ReplyDelete
  12. Here is another possible vector for inducing autism (not from the researchers here but from my own observations):

    Press Release:

    https://www.sciencedaily.com/releases/2018/04/180404114727.htm

    Paper:

    https://www.nature.com/articles/s41565-018-0085-3

    What this paper did was model placental cells/tissue and then expose the cells to metallic nanoparticles. What they found is that the nanoparticles caused DNA damage indirectly by causing autophagosomes to swallow up the nanoparticles and as a consequence release IL-6 (probably the biggest red flag cytokine with respect to autism). What was also interesting is that the DNA damage was astrocyte dependent which was confirmed when they removed the astrocytes. Blocking IL-6 or preventing autophagy also reduced the amount of DNA damage inflicted as well.

    Nanoparticles may be used in the future for many different medical purposes so understanding the pros/cons is obviously important. With respect to autism, there are many pollutants in industrialized societies that are small enough to potentially cause this kind of reaction in a developing fetus, just that I don't think anyone has done this kind of research before to look at indirect methods of genetic or epigenetic damage. In this particular case, it is the body's own immune system that does the damage so a study trying to look at the direct toxicity of some sort of industrial chemical or pesticide may overlook indirect methods of doing real developmental harm to the next generation of people.

    ReplyDelete
  13. Any opinions about ginko bilopa please.?

    ReplyDelete
    Replies
    1. Hi Amani,

      Why Gingko specifically?

      I know I had looked into Gingko a while back and I had found a few things that kept me from including it at the time (Don't recall specifics).

      Have you run an OAT test? What are you currently using? What are the main issues you are trying to address?

      Any supplement may help some people with ASD and have a negative effect on others, which is why trial and error plays a role in treating ASD (unless you have test results, like OAT testing).

      AJ

      Delete
  14. Am just trying to get help for my 9 years old daughter, and i recently got to know about this blog which i feel it is almost like a treasure giving answers to my all questions.i tried ginko once and it gave great results then had to stop it because it she had alot of hyperactivity. Then recently. Am thinking of it once again, because she kind have regressed, nowadays we are taking citicholin only 300 mg daily along with omega 3 .hace tried memexa 10 gave nice results then her acadaemic skills were greatly decreased , so i guess because of glutamte decrease so i stopped it and she is alittle better , but her inattention and math difficulty are our major concern , if you kindly tell me about oat test. Thank you

    ReplyDelete
    Replies
    1. Hi Amani,

      I totally get it, I was in exactly the same boat about 1.5 years ago.

      Amani, one of the best pieces of advice I've gotten in this while endeavor was from Tanya on this site. She suggested I get an OAT test done, and in retrospect, that has been one of the best things I have done.

      I didn't know what this was when Tanya mentioned it, so I researched and found out that the best one (I believe) is from Great Plains lab. I don't know where in the world you are, but pretty much you can get this done from anywhere.

      If you are in the US or Canada, contact a local integrative medicine practitioner and see if the work with GPL. Otherwise, you may want to reach out to GPL and see who they are partnered with in your area.

      If you are outside the US and Canada, check out the following links:

      https://www.greatplainslaboratory.com/order-a-test-international

      Now, the OAT test is a urine test, so easy to administer. You just have to collect some urine from your daughter, freeze it in the cup you get from GPL, and Fedex it to them.

      To learn more about the test, go the following link:

      https://www.greatplainslaboratory.com/organic-acids-test/

      The sample report looks like this:

      https://static1.squarespace.com/static/560ac814e4b067a33438ecea/t/5ac3917e352f533cbdd56a5c/1522766208767/New+Oat+Sample+Report+April+2018.pdf

      Amani, honestly, I would recommend doing an OAT test. It can help tell you some key things. It costs me $380 Canadian (don't know what currency you use).

      In terms of supplements, I use many and can't say which ones work and which ones don't, but overall I used a bit of knowledge and trial and error.

      You may want to look into supplements that help with mitochondrial health (i.e. Acetyl-L-Carnitine, R lipoic acid, Ubiquinol, etc.)

      I hope this helps Amani, and again, if I had one piece of advice for you, it would be to do the GPL OAT test - that may help you figure out a few key pieces of info in terms of what you would need to address.

      Hope this helps Amani!

      AJ

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    2. Thank you very much, am from Egypt, i appreiate your advice alot, but can you tell me more about what the test may reveal , in more detail please , thank you again

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    3. Hi Amani,

      I'm happy to help. At a high level, it can show if your daughter has:

      1. A gastrointestinal infection (bacteria or yeast), which can impact brain function

      2. Signs that may indicate a genetic issue

      3. Signs there may be nutritional issues

      4. Signs there may be mitochondrial issue

      5. signs there may be neurotransmitter issues

      6. Signs there may be issues with metabolism

      7. Signs there may be issues with detoxification

      8. Signs there may be amino acid issues.

      To really learn more, the following link takes you to a document that tells you what each reference interval means in the OAT test results:

      https://www.greatplainslaboratory.com/clinical-significance-of-the-oat

      To go back and forth into the 6 page document, you have to click on chevrons on the right and left of your screen, or move the progress bar at the bottom of your screen.

      Amani, I highly recommend you read each and every word of this document. You will learn a ton if you are new to this stuff.

      Rather than trying to make some decisions about which supplement to use with no diagnostic help, this test helps you figure out what may be a problem, and address it. Of course, you would still try other things as well that aren't a direct result of the OAT test, but why not try to address things you know are a problem than just shooting in the dark?

      Again Amani, if I could only give one piece of advice to someone in your position, it would be to do this test. Otherwise, you are just using trial and error.

      Peter and other folks on this board know much more than I do about ASD / treatments, so this is only my 2 cents, but I was exactly where you are 1.5 years ago and I've learned a ton by reading about ASD (this site is a godsend!).

      I hope this is helpful Amani, and I wish the best for you and your family!

      AJ

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  15. AJ, Amani, and Kritika,
    This is from a page on GPL’s site that I thought could also shed more detailed light on what all this testing can do:

    https://www.greatplainslaboratory.com/articles-1/2015/11/13/a-new-generation-of-organic-acid-testing-pushing-the-limits-of-detection-with-new-technology

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  16. I really can't thank you enough, i hace called a lab in my country and that test will be our first thing to do tomorrow's morning, feeling hoepful about that step .thank you tons

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  17. Hi Amani,

    I'm happy to help in any way that I can, and as the dad of an ASD girl, I completely get where you're coming from.

    The link that Tanya added really does provide even more reason to do an OAT test.

    Please do make sure that if you have someone other than GPL do the testing, that they are checking for all the same items GPL looks for.

    Best of luck Amani!

    AJ

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  18. https://www.ncbi.nlm.nih.gov/pubmed/10913502

    Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2's neurotrophic effects?
    Moore GJ1, Bebchuk JM, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB, Faulk MW, Koch S, Glitz DA, Jolkovsky L, Manji HK.
    Author information
    Abstract
    BACKGROUND:
    Recent preclinical studies have shown that lithium (Li) robustly increases the levels of the major neuroprotective protein, bcl-2, in rat brain and in cells of human neuronal origin. These effects are accompanied by striking neuroprotective effects in vitro and in the rodent central nervous system in vivo. We have undertaken the present study to determine if lithium exerts neurotrophic/ neuroprotective effects in the human brain in vivo.

    METHODS:
    Using quantitative proton magnetic resonance spectroscopy, N-acetyl-aspartate (NAA) levels (a putative marker of neuronal viability and function) were investigated longitudinally in 21 adult subjects (12 medication-free bipolar affective disorder patients and 9 healthy volunteers). Regional brain NAA levels were measured at baseline and following 4 weeks of lithium (administered in a blinded manner).

    RESULTS:
    A significant increase in total brain NAA concentration was documented (p < .0217). NAA concentration increased in all brain regions investigated, including the frontal, temporal, parietal, and occipital lobes.

    CONCLUSIONS:
    This study demonstrates for the first time that Li administration at therapeutic doses increases brain NAA concentration. These findings provide intriguing indirect support for the contention that chronic lithium increases neuronal viability/function in the human brain, and suggests that some of Li's long-term beneficial effects may be mediated by neurotrophic/neuroprotective events.

    ReplyDelete
  19. Given that some cancers and autisms share a genetic cause, and that in my specific case (which is not so specific as it covers up to 25 autism genes through transcription) the colorectal cancer form is very related, I have looked closer on some of the treatments for this.
    Also, as this blogpost mentions EPA vs DHA and we have discussed Krill Oil over a couple of other posts I thought the following paper might be of interest:

    "Krill oil extract suppresses cell growth and induces apoptosis of human colorectal cancer cells"

    Figure 1a and b shows how high dose EPA has a superior effect on reducing proliferation of cancer cells compared to DHA or arachidonic acid

    Figure 4 (two last staples) shows that EPA and Krill oil have a somewhat similar profile on inducing apoptosis in different cancer cell lines

    Figure 5 shows that Krill Oil has a unique property to change the mitochondrial membrane potential (MMP)

    "The results from the current study on MMP suggest that other components of the krill oil extract may play a role in the alteration of MMP, and the EPA induced cell apoptosis was possibly through other mechanisms rather than mitochondrial pathway. [..] krill oil also contains astaxanthin (provitamin E), flavonoids and vitamin-A. Different from fish oil, in the krill oil, EPA and DHA are bound to the phospholipids"

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004275/

    /Ling

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    Replies
    1. Ling,

      Krilloil had a very potent effect on me, but it scared me it felt kind of immuneamodulating. Very energizing, more potent than ritalin in that regard (atleast for me personally). Tended to have my brain always 'switched on'. Where as broccomax feels like it gives tons of brain energy but I can still relax, I cant seem to relax on krilloil, even at half the recommended dose lol. However I can see this being good for learning disabilities in exam periods.

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    2. I forgot to mention that the reason I posted something on cancer research is that for some reason a lot of the things that target colon cancer also have long term memory and cognitive enhancing properties.
      So, if EPA is superior to DHA, and Krill oil is similar to EPA in effect (but maybe different in its action) for colon cancer, one could speculate that the same applies for cognition.

      Aspie, it sounds like you got too much of something that you already have? It's interesting since Krill Oil didn't do much at all for me.

      I wish I could test it on my daughter, but the opened capsules taste so terrible that even making a one week trial would be very challenging.

      /Ling

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  20. Could this paper elucidate some of the reasons why DHA as a supplement doesn't seem to contribute to cognitive effects?

    "Here we show that oral administration of DHA to normal adult mice as lysophosphatidylcholine (LPC) (40 mg DHA/kg) for 30 days increased DHA content of the brain by >2-fold. In contrast, the same amount of free DHA did not increase brain DHA, but increased the DHA in adipose tissue and heart"

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596017/

    /Ling

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    Replies
    1. Ling, this is interesting and there are other studies showing the same thing. EPA levels in the brain do increase with regular supplements, but DHA does not. So current DHA products are pointless for brain conditions.

      LPC DHA may well be helpful for Alzheimer's, schizophrenia and other conditions that feature low DHA in the brain.

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    2. The more I look at this study, the more interesting it gets.

      What they almost doesn't mention (because their hypothesis was wrong), but which is obvious from the figures, is that their proposed formulation of DHA as lysophosphatidylcholine (called sn-1 DHA LPC) has approximately the same effect on the brain as krill oil (called sn-2 DHA LPC) while fish oil doesn't have much of an effect.
      And as seen in Figure 7, this means 40-100% upregulation of BDNF in five different areas of the brain. Figure 6B shows the difference in memory improvement in the mice.

      /Ling

      Delete

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