4G and Autism - Glutamine, Glutamate, GABA & GAD

This post is not about your IPad, it’s still about autism.

There are a few important substances that I have not fully addressed yet in this blog; as is often the case in biology, the names do all rather look alike.  A complete understanding of these 4 Gs will definitely help to understand the literature and hopefully separate science from pseudoscience and the voodoo.

We know for a fact that in autism some strange things are going on here, but it remains to be proved exactly what is going on, and whether all types of autism are similarly affected.  So it may be premature to visit the supplement shop.

 

The 4 Gs

Glutamine, like Creatine, is one of those chemicals that is widely used by body builders and sometimes given to children with autism.  It is an amino acid.

Glutamine is a precursor chemical to Glutamate.  Glutamate is a major excitatory neurotransmitter in the brain.

Glutamate is a precursor chemical to GABA, another very important neurotransmitter.

Glutamate is converted to GABA by the neuronal enzyme glutamate decarboxylase (GAD).

Glutamate is synthesized from glutamine via glutaminase, but after release in the synapse, glutamate is converted back into glutamine in glial cells, by glutamine synthetase.

 

Some Facts

Glutamine

Glutamine is known to help heal injuries and recover from abdominal surgery.  It was thought that this would extend to helping maintain the gut barrier, which is sometimes implicated in autism.  DAN type doctors use glutamine to “heal the gut”; however, when trials were made in Crohn’s disease, an inflammatory bowel disease similar to the type sometimes implicated in autism, supplementing with glutamine had no effect.
 

Glutamate

Glutamine + H2O

→ Glu + NH3

 

Glu is actually glutamic acid, the salts and esters of glutamic acid are called glutamates.  Often the literature mixes the terms glutamate and glutamic acid.

NH₃ is ammonia, which is also important and plays a role in some people’s autism theories.

Excessive glumate release is implicated in autism.  Glutamic acid is implicated in epilepsy, which is highly comorbid with autism.

Glutamate decarboxylase (GAD) is an enzyme that catalyzes the conversion  of glutamate  to GABA and CO₂.

HOOC-CH₂-CH₂-CH(NH₂)-COOH → CO₂ + HOOC-CH₂-CH₂-CH₂NH₂

Where HOOC-CH₂-CH₂-CH₂NH₂  is GABA (Gamma-Aminobutyric acid)

 
GABA

GABA is another amino acid and important neurotransmitter.  It is also known to regulate muscle tone, which is often affected in autism.

GABA works by binding at receptors, this binding causes the opening of ion channels to allow the flow of either negatively charged chloride ions into the cell or positively charged potassium ions out of the cell.

There are two classes of GABA receptor : GABA_A and GABA_B

The drug Baclofen is an agonist for the GABA_B receptors. A version of this drug called Arbaclofen is being developed as a treatment for autism and Fragile X.

Baclofen is a drug to treat spasticity, which is a condition where there can be strange effects on the muscles like spasms, stiffness and tightness.  Some people with ASD have a tendency to clasp their hands and fingers in a strange tight claw-like fashion and indeed some walk with an odd gait.  That would appear to me to be a form of spasticity.  Baclofen was stumbled upon by accident as a possible autism drug, where it would treat a form of mental spasticity.

Baclofen also has a long forgotten secondary effect that interested me; it stimulates the production of GH (Growth Hormone).  GH does appear to be implicated in autism along with IGF-1 and its analogues.

An antagonist of the GABA_A receptor, bumetanide, works by blocking the NKCC1 cation-chloride co-transporter, and thus decreases internal chloride concentration in neurons. In turn, this concentration change makes the action of GABA in some people with autism, returning it from excitory to inhibitory, where is should be.

I think it is clear that GABA plays a major role in some types of autism.

Recent Studies

As noted in previous posts, some very practical research comes out of Iran these days.

Increased Glutamate and Homocysteine and Decreased Glutamine Levels in Autism: A Review and Strategies for Future Studies of Amino Acids in Autism

"2.1. Glutamate

Glutamate is a major excitatory neurotransmitter in the brain. The high level of plasma glutamate level especially in children with normal IQ is supposed to be a diagnostic screening test. The increased plasma level in adults with autism is also reported. Higher glutamate level is not limited to plasma, and some studies confirmed its higher level in some brain regions (amygdala-hippocampal regions but not in parietal region) of patients with autism compared to the controls. The increased plasma glutamic acid is not limited to patients with autism, but its level is increased in their siblings and parents. "

"2.2. Glutamine

The low level of plasma glutamine level is suggested as a screening test for detecting autism in children especially those with normal IQ. The decreased level has been reported before in all children with autism."

A very recent study by King's College London looked at the level of glutamate and glutamine in adults with ASD using clever proton magnetic resonance spectroscopy in two brain regions. 

Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a [1H]MRS study 

They found reduced levels of the combined signal of glutamate and glutamine in autism versus the control group.  It all sounds very clever until you get to the discussion part, where they say:-

"Hence, it could be that serotonergic abnormalities underlie the differences in Glx we observed—either indirectly via influences on neurodevelopment or through direct action on glutamate metabolism."

This may be the case of over-analyzing certain variables, because the technology exists, even though you can only understand 20% of the problem.  The end result is lots of complicated looking data and analysis that may actually lead nowhere.

A reality check is required.  We have to come back to definitive facts otherwise the research is just generating confusion.

We already know serotonergic abnormalities are present in autism.  We know that drugs that increase brain serotonin, such as LSD and Prozac, improve autistic behaviours.  So the researchers at Kings College have very likely just measured a consequence of these abnormalities.  As a result, the glutamate/glutamine issue may indeed join the long list of consequences, rather than causes of autism.

 

The fever effect (again)

Another reason for this post is that both Glutamine and Glutamate have been put forward as possible explanations for the fever effect in autism; that is a reduction in autistic behaviour when person is sick, with a high temperature.

The fever effect is so dramatic in some people, that it would be ever so easy to validate a hypothesis.  In doing so, you would open the door to a very useful therapy for many people.

Does infectious fever relieve autistic behavior by releasing glutamine from skeletal muscles as provisional fuel?

 

This paper was published in the Journal Medical Hypotheses, but the full version is not always available free, the first link is to the author’s own site.  It is a very thorough analysis and worth a read, but in the end the author seems to disprove his own hypothesis.

A preliminary version of this paper was sent to several hundred ASD practitioners (DAN Doctors) formerly listed on the ARI site, for feedback. Fourteen replies suggest ASD practitioners commonly give oral glutamine to heal the intestines, from 250 mg to 8 g/day, with few side effects (some hyperactivity) but few notable improvements in behavior.

So now on to the next candidate, glutamate.

The second hypothesis is by Ghanizadeh, the Iranian author of the paper I referred to earlier.

Could fever and neuroinflammation play a role in the neurobiology of autism? A subject worthy of more research.

Abstract

Autism is neuropsychiatric disorder in which a hyperglutamate state may play a role. It is suggested here that fever or hyperthermia may be able to alter glutamate levels in the brain and may therefore be able to impact on the symptoms of autism. More study on this possibility is clearly warranted.

Conclusion

Of the 4 Gs, I am sticking with GABA as the key one, but I will not be buying any GABA supplements, even though they do exist.  Some DAN-type doctors favour Glutamine supplements, even though some well-known “holistic” type doctors like Dr Mercola say specifically not to give it to kids with ASD and ADHD.

I have no doubt that glutamate plays an important role in autism, but as with GABA it is not just a matter of swallowing some.

There is a line to be drawn between science, pseudoscience and pure voodoo. For the time being, you have to find this line yourself.

Epigenetics and Autism

I have touched on the subject of epigenetics in a previous post; it is a new area of science that shows how the environment can modify your genes.  Rather than you being purely a product of your parents’ genes, you actually also have both your own environmentally acquired epigenetic changes, and some of the acquired epigenetic changes of your ancestors.

These acquired epigenetic changes are caused by things like emotional trauma, chemical insults and even smoking.

Epigenetic control systems generally involve three types of proteins: “writers”, “readers”, and “erasers.” Writers attach chemical marks, such as methyl groups (to DNA) or acetyl groups (to the histone proteins that DNA wraps around). So-called “readers” bind to these marks, thereby influencing gene expression; erasers remove the marks.

 

In theory epigenetic changes should be reversible, but this is not simple.

You may recall in an earlier post about asthma, we learnt that it is very hard to treat former smokers.  Once a person has smoked heavily, a change occurs whereby the body remains in permanent oxidative stress and conventional asthma drugs are not very effective.  The fact that the person gave up smoking 20 years previously does not help.  The only way to treat the patient is to first treat them with an antioxidant and NAC was the most effective; even then the result is not so good.

Epigenetics and Autism

It is said that autism is caused by a combination of genetic and environmental factors; but it might be better stated that autism is caused by genetic and epigenetic factors.  Those epigenetic factors would include all the accumulated environmental factors affecting that person and his ancestors.

As modern life becomes more distant from the village life of our ancestors, you can imagine a gradual build-up of environmental and stress factors.  If you cannot erase some of those marks, you will reach a point where the “tainted” DNA will produce aberrations.  Such aberrations might trigger cancer in one person and autism in another. 

Epigenetic Drugs

Cancer was identified very early as being a likely consequence of epigenetic changes.  Cancer research is very well funded and some epigenetic drugs are already available.  The idea is that epigenetic drugs should selectively target reversible epigenetic changes

A particular problem is that the drug has to act very selectively.

If you were able to erase all those chemical marks on someone’s DNA, there would most likely be some unwanted and unanticipated changes.

One pioneer in this field is a US firm called Acetyton Pharmaceuticals.

 

Epigenetic Research in Autism

The good news is that research has recently started in this area, and it might eventually lead to the possibility of reversing some of those unwanted epigenetic changes.

Here is rather heavy study from Kings College in London:-

Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits

 

Autism spectrum disorder (ASD) defines a group of common, complex neurodevelopmental disorders. Although the aetiology of ASD has a strong genetic component, there is considerable monozygotic (MZ) twin discordance indicating a role for non-genetic factors. Because MZ twins share an identical DNA sequence, disease-discordant MZ twin pairs provide an ideal model for examining the contribution of environmentally driven epigenetic factors in disease. We performed a genome-wide analysis of DNA methylation in a sample of 50 MZ twin pairs (100 individuals) sampled from a representative population cohort that included twins discordant and concordant for ASD, ASD-associated traits and no autistic phenotype. Within-twin and between-group analyses identified numerous differentially methylated regions associated with ASD. In addition, we report significant correlations between DNA methylation and quantitatively measured autistic trait scores across our sample cohort. This study represents the first systematic epigenomic analyses of MZ twins discordant for ASD and implicates a role for altered DNA methylation in autism.

 

For those of you who prefer some milk in your coffee, those helpful people at the MIND Institute in Sacramento have produced a series of video lectures on this very subject.

Here is the full list:

Environmental Epigenetics: New Frontiers in Autism Research

 and here is one particular video.

How might epigenetics relate to the etiology of ASD?


  

Conclusion

Epigenetics would help explain the increasing prevalence of ASD in the most developed countries.  It also opens the door to potentially highly effective treatment mechanisms to many currently incurable conditions.

Perhaps, by chance, one of the new epigenetic drugs developed for cancer will have a positive effect in ASD.

 
 

 

Long Term Bumetanide Use in Autism

This blog started life after I read about a clinical trial of the diuretic bumetanide to treat autism.  In the following 12 months the authors of that study, Ben-Ari and Lemmonier, have been busy building up their scientific case.  They published two further papers:-

 

 

Treating Fragile X syndrome with the diuretic bumetanide: a case report. 

We report that daily administration of the diuretic NKCC1 chloride co-transporter, bumetanide, reduces the severity of autism in a 10-year-old Fragile X boy using CARS, ADOS, ABC, RDEG and RRB before and after treatment. In keeping with extensive clinical use of this diuretic, the only side effect was a small hypokalaemia. A double-blind clinical trial is warranted to test the efficacy of bumetanide in FRX.

This single case report showed an improvement of the scores of each test used after 3 months of treatment. Double-blind clinical trials are warranted to test the efficacy of bumetanide in FRX.

 

Improving emotional face perception in autism with diuretic bumetanide: A proof-of-concept behavioral and functional brain imaging pilot study.

 

Clinical observations have shown that GABA-acting benzodiazepines exert  paradoxical excitatory effects in autism, suggesting elevated intracellular chloride (Cl-)i and excitatory action of GABA. In a previous double-blind randomized study, we have shown that the diuretic NKCC1 chloride importer  antagonist bumetanide, that decreases (Cl-)i and reinforces GABAergic  inhibition, reduces the severity of autism symptoms. Here, we report results from an open-label trial pilot study in which we used functional magnetic  esonance imaging and neuropsychological testing to determine the effects of 10 months bumetanide treatment in adolescents and young adults with autism. We show that bumetanide treatment improves emotion recognition and  enhances the activation of  brain regions involved in social and emotional perception during the perception of emotional faces. The improvement of emotion processing by bumetanide reinforces the usefulness of bumetanide as a promising treatment to improve social interactions in autism.

 

My experience after 12 months of Bumetanide

Bumetanide continues to have a positive effect on Monty, aged 10 with ASD, which I would summarize as a marked increase in awareness or “presence” or a lack of “absence” from the world.  Improved social interactions may have followed, but are secondary.

My own impression is that the effect peaks and then reduces somewhat.  This also appears to be the case with NAC and Atorvastatin.  I think the body is adjusting to the new treatments, via feedback loops.  This is inevitable, it is just a matter of human physiology.  If the above MRI study shows a long term change in brain function, then great.

I hope that my future therapies will be more disease changing, this does look to be possible.  Early signs are promising. 

 

My experience of 12 months blogging

My doctor mother asked me over Christmas how many people have been reading my blog and acting on it.  The answer is about 6,000 page views a month, but I suspect less than 10 people have even tried Bumetanide, nobody has tried Atorvastatin, and a few tens have tried NAC.

I think people are frightened of drugs.  Supplements are OK and any kind of unusual diet is great.

I think if I proposed a diet of baked beans, fried eggs and bacon I would have a much bigger following. Luckily that was not my objective.

With the advent of the internet, simple drugs like diuretics are as easy to buy as supplements like NAC; I doubt you are going to get into trouble for having an unauthorized diuretic in the bathroom cabinet.

Supplements are not subject to the same manufacturing standards as drugs and there are pretty strange things sold as “supplements”.

I will continue to develop my own therapy for classic early onset autism and when I finish, I will patent it and produce it as an orphan drug.  Orphan drugs are for rare diseases, where there is no other treatment.  They have less daunting regulatory requirements, meaning you do not need $25 million to develop them. In the EU you need a serious condition affecting fewer than 5 in 10,000 people; across the EU that equates to 250,000 people.  If you narrowly define my target autism phenotype, with biomarkers you end up within this limit.

Unfortunately, if you want to patent something, you have to keep it secret.  I did discuss all this with the venture capital firm that commercializes the intellectual property of my old university plus that of Cambridge, Oxford and UCL. The conclusion was to either give it to the world for free, or to commercialize it.  Giving it for free clearly has zero impact, so it has to be Plan B.

So the blog continues, but it will not contain all the clever stuff.

Next steps

I have also been busy in the last twelve months, having taken my inspiration from the Frenchmen, Ben-Ari and Lemmonier.  I have had my own “breakthroughs”, by applying the research and some imagination.

While you cannot totally cure genuine autism, you can go a long way, far further than I would have dared to believe possible.

You can treat the most difficult issues such as absence, anxiety, aggression and SIB.  Odd behavioural traits like obsessions and compulsions can be greatly reduced.  The combined effect is definitely a much happier person.

I think there is much more possible in areas like mood, confidence, creativity, sociability and indeed cognitive performance.

Bumetanide was a very important first step, but in itself it is far from a “cure”.  In combination with some other safe drugs, the result will indeed be remarkable.

The final element will be time itself.  The human brain does not come ready programmed; the first few years of childhood are used to establish full brain function.  In autism, during these important first few years the brain was running in “safe mode”, all sorts of important connections were never made and some were lost.  The brain does remain plastic throughout life and so it has the potential to make some of these missing connections.

The drug treatment has to deal with oxidative stress, neuro-inflammation, several ion channel/transporter dysfunctions and the tricky area of central hormonal hypofunction/dysfunction.

Note that not all people with autism respond to Bumetanide. Only a large clinical trial will show what percentage are responders.  In the same way, I expect only a minority of those diagnosed with ASD by current psychiatric measures will respond to my drug; but it would be possible to identify them based on biomarkers and case histories. 


 

Autism Pathology as a Venn Diagram

Source: Peter Research                     

Notes

 

Oxidative stress increases neuro-inflammation

Neuro-inflammation increases oxidative stress

Both oxidative stress and neuro-inflammation contribute to central hormonal dysfunction,

e.g. stress reducing D2 levels that stop T4 converting to T3 in the brain

One year after starting my investigation, I thought it would be useful to sum up Classic
Autism in a simple form.  I chose a Venn diagram.  At school your kids probably have just 
two overlapping circles.  If you have four variables you need to use ellipses.  Where all four variables are in play, is the area where all four ellipses overlap.  This is untreated classic autism.

 

Once you successfully treat any of the four trouble areas (Neuro-inflammation, oxidative
stress, channelopathies and hormonal dysfunction in the brain) you can modify the disease
and move to a happier part of the diagram. 





Amyloids, APP, ADAM17 and Autism

Tonsil biopsy in variant CJD, source: Wikipedia

Amyloid may sound like someone’s name, but in fact it is something rather sinister and is related to many brain disorders.  It appears that, at least in severe cases, they may be implicated in autism, or least the precursor is.

Proteins that are normally soluble undergo a process called amyloidosis, which makes them insoluble and allows deposits to accumulate in various organs, including the brain.  There are many known examples, including Alzheimer’s  and Mad Cow Disease (Creutzfeldt–Jakob disease).  A number of years ago there was a huge public health scare in the UK, when humans were affected by Mad Cow Disease, after eating the brains of cows in processed food.

Symptoms vary widely, depending upon where in the body amyloid deposits accumulate. Amyloidosis may be inherited or acquired.

The precursor to amyloid is naturally called  Amyloid Precursor Protein (APP).

APP exists in all of us and is not necessarily bad.  Its function is not fully understood (see later in this post). 

Alzheimer’s                           Autism

Affects female > Mmale                                   Affects male > female 

Brain atrophy                                                     Macrocephaly

                                                                              (enlarged brain in child)

Amyloid plaques  

Degenerative                                                      Decline followed by stable 

High αβ, low sAPPα                                           High sAPPα, low αβ

           

 
Amyloid Precursor Protein (APP)

The gene related to Amyloid Precursor Protein (APP), was only identified in 1987 and the biology surrounding it is only very partially understood.  Much of the experimental work is related to Alzheimer’s, but some of these researchers are also looking at implications for autism.

For the bold, here is a very recent paper on APP:-

Biology and pathophysiology of the amyloid precursor protein

A power-point style presentation is here:-

Brain Amyloid Precursor Protein (APP) Neuronal Markers in Children with Autism

The research proved the hypothesis:-

APP metabolites follow nonamyloidgenic pathway (i.e., high sAPP, sAPPα, low Aβ 40) in brain tissue of children with autism, compared to age matched controls

Here is the data:-

 

 

For those of you who want to read a full paper by the same authors from Indianapolis, here it is:-
 

Increased Secreted Amyloid Precursor Protein-a (sAPPa) in Severe Autism: Proposal of a Specific, Anabolic Pathway and Putative Biomarker

 

Terminology

Biologists do make their work sound very complicated; generally it is the terminology that may make it look unintelligible on first reading.  Just read it again and look up the confusing terms.  They also seem to have up to 5 different names for the same molecule.

Compared to other areas of science like Fluid Mechanics, which I had to study, and Wikipedia rather understated describes as “Fluid mechanics can be mathematically complex”,  biology is just a lot of knowledge; none is really intellectually challenging, at least not until the amyloids start growing.

Just use the amazingly up to date resources of Wikipedia.

Aβ   =  beta amyloid   = amyloid β-peptide     The most common isoforms are Aβ₄₀ and Aβ₄₂

βAPP = β-amyloid precursor protein = amyloid-β precursor protein  = AβPP

 sAPPα = soluble APPα = soluble amyloid precursor protein α

β-secretase = Beta-secretase 1  = BACE1 = beta-site APP cleaving enzyme 1 = beta-site amyloid precursor protein cleaving enzyme 1

 γ-secretase = Gamma secretase

Gamma secretase can cleave APP in any of multiple sites to generate a peptide from 39 to 42 amino acids long.

Generation of the 42  Aβ (amyloid β-peptides) that aggregate in the brain of Alzheimer's patients requires two sequential cleavages of APP.  Extracellular cleavage of APP by β-secretase (BACE) creates a soluble extracellular fragment and a cell membrane-bound fragment referred to as C99. Cleavage of C99 within its transmembrane domain by γ-secretase releases the intracellular domain of APP and produces Aβ (amyloid-β).

However a single residue mutation in APP reduces the ability of β-secretase to cleave it to produce amyloid-beta and reduces the risk of Alzheimers and other cognitive declines.

Inhibitors of amyloid deposition include the enzymes responsible for the production of extracellular amyloid such as β-secretase and γ-secretase inhibitors.  Currently the γ-secretase inhibitors are in clinical trials as a treatment for Alzheimer's disease.

 

Amyloid Precursor Protein

Amyloid precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export. APP is best known as the precursor molecule whose proteolysis generates beta amyloid (Aβ), a 37 to 49 amino acid peptide whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease

Biological function

Although the native biological role of APP is of obvious interest to Alzheimer's research, thorough understanding has remained elusive.

Synaptic formation and repair

The most-substantiated role for APP is in synaptic formation and repair; its expression is upregulated during neuronal differentiation and after neural injury. Roles in cell signalling, long-term potentiation, and cell adhesion have been proposed and supported by as-yet limited research. In particular, similarities in post-translational processing have invited comparisons to the signaling role of the surface receptor protein Notch.

APP knockout mice are viable and have relatively minor phenotypic effects including impaired long-term potentiation and memory loss without general neuron loss. On the other hand, transgenic mice with upregulated APP expression have also been reported to show impaired long-term potentiation.

The logical inference is that because Aβ accumulates excessively in Alzheimer's disease its precursor, APP, would be elevated as well. However, neuronal cell bodies contain less APP as a function of their proximity to amyloid plaques. The data indicate that this deficit in APP results from a decline in production rather than an increase in catalysis. Loss of a neuron's APP may affect physiological deficits that contribute to dementia.

Iron export

A different perspective on Alzheimer's is revealed by a mouse study that has found that APP possesses ferroxidase activity similar to ceruloplasmin, facilitating iron export through interaction with ferroportin; it seems that this activity is blocked by zinc trapped by accumulated Aβ in Alzheimer's. It has been shown that a single nucleotide polymorphism in the 5'UTR of APP mRNA can disrupt its translation.

The hypothesis that APP has ferroxidase activity in its E2 domain and facilitates export of Fe(II) is possibly incorrect since the proposed ferroxidase site of APP located in the E2 domain does not have ferroxidase activity.
 

Hormonal regulation

The amyloid-β precursor protein (AβPP) and all associated secretases are expressed early in development and plays a key role in the endocrinology of reproduction – with the differential processing of AβPP by secretases regulating human embryonic stem cell (hESC) proliferation as well as their differentiation into neural precursor cells (NPC). The pregnancy hormone human chorionic gonadotropin (hCG) increases AβPP expression and hESC proliferation while progesterone directs AβPP processing towards the non-amyloidogenic pathway, which promotes hESC differentiation into NPC.

AβPP and its cleavage products do not promote the proliferation and differentiation of post-mitotic neurons; rather, the overexpression of either wild-type or mutant AβPP in post-mitotic neurons induces apoptotic death following their re-entry into the cell cycle. It is postulated that the loss of sex steroids (including progesterone) but the elevation in luteinizing hormone, the adult equivalent of hCG, post-menopause and during andropause drives amyloid-β production and re-entry of post-mitotic neurons into the cell cycle.

Arthritis

Recently, amyloid precursor protein (APP) origin was demonstrated with arthritogenic animals. The source noted is breakdown of immune complexes, where the amyloid aggregates are left degraded and bind together to form coil like structures that are not reabsorbed. Also, it induces secondary inflammation, which may cause local damage.

ADAM17

ADAM17 is understood to be involved in the processing of tumor necrosis factor alpha (TNF-α) at the surface of the cell. This process, which is also known as 'shedding', involves the cleavage and release of a soluble ectodomain from membrane-bound pro-proteins (such as pro-TNF-α), and is of known physiological importance. ADAM17 was the first 'sheddase' to be identified, and is also understood to play a role in the release of a diverse variety of membrane-anchored cytokines, cell adhesion molecules, receptors, ligands and enzymes.

Conclusion

Even though it does sound complicated, there are some conclusions.

Amyloid Precursor Protein (APP) can either be processed towards so-called amyloidogenic pathways in the brain that lead to Alzheimer’s, or it can follow so-called non-amyloidogenic pathways, as appears to be the case in autism.  The direction taken seems to depend on α, β and γ–secretases, which are themselves regulated by neurotransmitters and other signalling molecules.

But why are there elevated levels of APP in autism?

As is often the case in autism research, some are thinking biomarker and some are thinking about therapeutic interventions.  I am with the latter.

By the way, now we have dealt with Amy, what about Adam? (the final chart above)

Functional ADAM17 has been documented to be expressed in the human colon, with increased activity in the colonic mucosa of patients with ulcerative colitis, a main form of inflammatory bowel disease.  But remember, that paper by Wakefield was retracted and so there should not be evidence linking autism with colitis.  Tell Adam to keep quiet.

ADAM17 = ADAM metallopeptidase domain 17  =  TACE  = (tumor necrosis factor-α-converting enzyme) = TNF α-converting enzyme 

TNF are a group of cytokines that cause cell death.