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Sunday 22 December 2013
Friday 20 December 2013
Amyloids, APP, ADAM17 and Autism
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:-
A power-point style presentation is here:-
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:-
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
β-secretase = Beta-secretase
1 = BACE1 = beta-site APP cleaving enzyme 1 = beta-site amyloid precursor
protein cleaving enzyme 1
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
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.
TNF are a group of cytokines that cause cell death.
Wednesday 18 December 2013
An Acquired Channelopathy
Source:Wikipedia
For the psychologists among you, and self-taught ABA parents like me, you will know what is a meant by an "acquired behaviour". So once a child has learnt a behaviour, that resulted in something the child found rewarding, the behaviour will repeat.
Once learnt, it is difficult to get rid of unwanted acquired behaviours. An example in autism would be self-injury.
In an earlier post, we learnt that children at risk of developing asthma, if identified and treated with a mast cell stabilizer, could be prevented from developing asthma. Once you have had one asthma attack, more will follow.
Today, I learnt that you can acquire a channelopathy, that is to say an ion-channel disease that is normally caused by your genes.
"We do know that in some forms of epilepsy, once someone has a seizure they tend to have more. Our findings from this study suggest that something about the brain changes that can lead to this increased tendency to have a seizure. Our study shows that an important change occurs in calcium channels that help to transmit this abnormal activity throughout the brain."This means, at least in some types of epilepsy, the first seizure permanently changes (damages) the brain. Thereafter, the affected ion channels function as if that person had a gene mutation.
This is important for the study of autism because we know that there are ion-channel abnormalities. If you could identify these channelopathies, that would be the first step towards treating them, and reversing the associated behaviours.
If these channelopathies were not predetermined by genetics, rather some were acquired, that would be very important. Then you could look at how, when and why they were acquired.
It might be that the channelopathies caused by rare inborn genetic mutations associated with conditions like Timothy Syndrome, are not so rare after all. It is just that the channel mutated without the "faulty" gene. So genetic testing will not identify it.
Tuesday 17 December 2013
Autism & Self-Injurious Behaviour (SIB)
For parents
more severely affected by autism, one of the most difficult things to deal with
is anger, aggression and self-injurious behaviour (SIB). SIB is sometimes rather politely referred to
as challenging behaviour.
In the case of Monty, aged 10 with ASD, we have
overcome these problems (for now at least); but for other people have to
struggle on with them, on a daily basis.
SIB can affect any person with autism, whether they are severely, moderately or mildly affected otherwise. Left untamed, I am reliably informed, it may return in adulthood.
So, for those people, who do not want to follow the “novel”,
but science-based, interventions discussed elsewhere in this blog, here is what
the experts have to say:-
From the US (an excellent paper) :-
From the UK:-
Monday 16 December 2013
Comorbidities in Autism and the Curious Cleaning Lady
We have a cleaning lady who comes each week to help keep our
house in order. She also understands the
value of comorbidities. She is one of my independent observers, in changes in the
behaviour of Monty, aged 10 with ASD. She
has a friend, whose husband was diagnosed with early-onset Alzheimer’s.
Alzheimer’s is not autism, but they are both examples of
brain damage.
Still in his early 50s, the husband does not recognize his
children and cannot leave home. The expert
Professor, treating him privately, was not halting the rapid decline.
So the cleaning lady asks me about all my investigations and
decides that she might as well tell her friend.
She decided to suggest the antioxidant NAC and the cholinergic stimulant
nicotine.
Well, after NAC, the husband was able to make it to the WC
and do his business. A small step
forward.
After a day with the nicotine patch, things really changed
so much that the family decided that they should seek a second opinion, this time
from a doctor, yet to publish a book.
Doctor number two decided that it is not Alzheimer’s after all, and
the prescribed medicines of the last three years were only making things worse. And the new therapy? Nicotine patches.
Conclusion
The conclusion is self-evident.
The next related conditions I will be investigating are cluster
headaches, febrile seizures and absence seizures.
Wednesday 11 December 2013
Assessment Week at School and Cognitive Enhancement in Autism
·
Highly
subjective, or ineffective, rating scales for autistic behaviours
·
Lack
of biomarkers, or any other marker, to target a specific sub-types(phenotypes
of autism
·
Very
small sample sizes and often amateur execution, meaning the results cannot be
replicated
I think one
of these problems has a ready solution, at least for verbal primary school children with ASD.
Assessment Week
Last week,
Monty aged 10 with ASD, had assessment week at school. The academic subjects he participates in, are
Maths, English and Science. We have
chosen to skip Geography, History and French.
Monty already has another second language.
Following
the tests at school, I decided to make a test of my own. I stopped all of my therapies and waited to
see what would happen and if anyone would notice.
The first
therapy I had to reintroduce was bumetanide, which in his case makes him far
more aware of himself and his surroundings; it makes him more “present”. The reason for this was, for the first time
in years, on day one, he forgot to go to the toilet and peed in his pants. A coincidence? I think not.
Also, when I told him that I was going out, instead of the expected “see
you later, Dad” I got “see you Monday”.
Then the
next day having restarted bumetanide we drive to school. I hear lots of relevant comments like “There’s a Peugeot
lion taxi car”, “The soldier has a gun, that fires bullets”. The day before there were no comments at all.
But the day
at school was not so good; all the stereotypy with his hands and fingers
returned, so while the day was not hard for his assistant, she said it was hard
for Monty. He was commenting, like the
things he could see through the window of his classroom, but work was not
good. Handwriting degenerated to
oversized sloppy writing, that did not follow the lines on the paper. In the afternoon,
I reinstated NAC, just in time for the arrival of his assistant who works with
him at home, following an ABA-style programme.
During the rest of the afternoon, all stereotypy with his hands and
fingers disappeared, just as expected.
Today, I met
the school teacher and not only were his grades As and Bs, but he finished his
tests much faster than most of the other children. This is remarkable, because he has never
received any real academic grades before; the teachers did not think it fair to
give him grades. I should point out that
Monty is at least 2 years older than his classmates; but then he was pretty
much entirely non-verbal until he was 4 years old, so he has lost a lot of learning time.
The relevance
of all this is that while psychological and behavioral testing is very
subjective, basic cognitive testing, as practiced in schools around the world,
is very well understood, fair and easy to replicate.
With
children who are verbal, can read a bit, write and do some very basic maths, a
simple cognitive test, measuring these basic skills, assessing both accuracy and
speed would produce a pretty good surrogate index of cognitive functioning. You could easily use such an index to measure
the effectiveness of a drug in autism.
If large scale trials were done in Special Schools, this could work
really well. One week the class is on the
placebo and the next week on the trial drug.
Then you could have trials with several hundred participants.
I think
coming up with measurements for things like “social withdrawal”, as is currently
done, is far too esoteric. Let’s go back
to the three Rs (reading, writing and arithmetic).
Nootropic drugs
I find it
more than a coincidence that several of the autism drugs I am investigating,
happen to be classed as nootropic.
Nootropic drugs are cognitive enhancers.
I have
demonstrated that as you improve autism, you increase cognitive function; but
perhaps as you improve cognitive function, you improve autism. If this were true, it would open up new
avenues for investigation.
There is an
underground scene of cognitive enhancers, and if you probe the internet, you
will readily find what works and what does not.
On the serious research front, here is a recent paper
that is very comprehensive:-
Tuesday 10 December 2013
Autism, a Dynamic Encephalopathy, Indeed
With a title
like that, not many people will stumble upon this post with Google.
So, for the
hard-core of readers, today I am going to develop an idea of Martha Herbert,
the pediatric neuroscientist from Harvard, who writes a lot about autism.
Incidentally,
most researchers do not like publicity, and particularly those looking at
autism. Martha, herself makes some side
remarks as to why this is; as I suggested in earlier posts it dates back 10+
years to a certain Dr Wakefield.
“A further barrier to considering the body’s impact on the
brain was the reaction to the work of Wakefield, who argued not only that
there was a link between autism
and vaccines but
also that this
link was mediated through the gastrointestinal system. For the better part of a
decade any attempt to discuss gastrointestinal or immune issues with
autism was construed as a support of Wakefield’s vaccine hypothesis, and it
was difficult to discuss, let alone get funding for, clinical or research
observations about these problems. One
way around the essentially taboo character of somatic problems in autism was to treat them as coincidental
symptoms. For example, one could
talk about gut problems provided one made it clear that they did not cause the autism in the brain. Improvement
after treatment of gut problems, which is often observed, would then be
explained as a consequence of reduction of pain and discomfort, but not of
any direct impact on core brain
mechanisms generating autistic behaviors.”
Another fearless autism researcher, not shy to voice his opinions by blog and
tweet, is Paul Whiteley, in Sunderland. Paul
is very much a believer in the role the gut/diet in autism, he and Paul Shattock are
the driving force behind the gluten and casein free diet as a therapy for
autism. Given what Martha writes above,
and the association between Shattock and Wakefield, is it surprising that the GCF
diet remains on the fringes? I know some
parents who wholly endorse it.
Here is a link to one of Martha’s recent works, for Herbert fans:-
Dynamic Encephalopathy
It was Martha who called autism
a dynamic Encephalopathy.
Encephalopathy just means a brain disease.
What she means is that over
time autism changes, day to day and year to year. Just as during fever, autism symptoms may
wane, other environmental provocations may cause flare ups. With age come hormonal changes that will inevitably
change the central hormonal homeostasis, I hope for the better, as generally is
the case.
Other than being a fancy word, Encephalopathy,
is probably a much better word than autism.
There are many types of Encephalopathy and there are multiple causes, it
refers to a syndrome of global brain dysfunction; this syndrome can have
many different organic and inorganic causes.
As with autism the hallmark of encephalopathy is an altered mental state.
If you have not already
opened up Wikipedia, I suggest you do.
From my desk research and
primary research, I know that one factor behind this encephalophy is chronic inflammation,
otherwise known as neuroinflammation.
At this point, we should look at
what neuroscience can tell us about neuroinflammation
The
Dana Foundation is a private philanthropic organization committed to advancing
brain research. Founded in 1950 and with
$230+ million in assets I think they should be a good source. Here
is an excellent paper, that is written for non-scientists.
Among the many interesting
insights are these:-
“Until
recently the CNS and peripheral immune system were thought to operate
independently.”
“However, new research has led to
important advances in our understanding of how immune-related events in the
periphery can influence CNS processes, thereby altering cognition, mood, and
behavior, and these advances are suggesting that inflammation may have
important long term implications for the brain.”
“Inflammation
in the body can lead to inflammation in the brain”
“The same cytokines
that participate in producing the inflammatory response in the body also
initiate the communication process to the CNS. They accumulate in the
bloodstream and thereby travel to the brain”
“They cross into the
brain in regions where the barrier is weak, and they bind to receptors on the
insides of the cerebral vascular blood vessels, thereby inducing the production
of soluble mediators within the epithelial cells that can cross into the brain.”
“In addition, there
are neural as well as blood-borne communication routes. For example, there are cytokine receptors on
nerves, such as the vagus, that innervate peripheral immune organs, and these
nerves communicate to the brain and are activated during infection.”
“During a normal
infection, neuroinflammation and the resulting adaptive sickness behaviors
persist only for several days. However, if these responses become exaggerated
or prolonged, the outcomes may well become established, leading to cognitive
impairment instead of brief memory disruption,”
“… physiology can
become pathology when a set of processes designed to be relatively brief
becomes prolonged.”
“However, peripheral
inflammation is highly complex and involves many immune cells and their
products. Existing anti-inflammatory drugs often target only one of these. For
example, non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen,
inhibit only a hormone, prostaglandins, leaving other actors in inflammation
(cytokines, chemokines, etc.) untouched.”
“A second way that
central neuroinflammation could be prolonged is less obvious. The CNS may come
to over-respond to the same signal from the peripheral immune system. As noted
above, microglia and the cytokines they produce when activated are at the core
of the neuroinflammatory response that produces sickness behaviors. If
microglia were to become “sensitized,” which means they respond in exaggerated
or prolonged fashion, then sickness behaviors would become intensified and
prolonged—pathology instead of physiology.”
“Most encouragingly,
studies in numerous animal models show that the development and expression of
chronic pain can be blocked with drugs that inhibit either microglial
activation within the spinal cord, or the inflammatory cytokines that microglia
produce.”
“In addition,
microglia also can become sensitized without a prolonged peripheral
inflammation. For example, aging appears to sensitize microglia so that
microglia, particularly in the hippocampus, respond in exaggerated fashion to
input. Thus, neuroinflammation produced by surgery, peripheral infection, and
the like, is greatly exaggerated in aged subjects. Correspondingly, aging also
augments the chances of depressive behaviors, cognitive impairments, and pain
produced by peripheral inflammatory events. Encouragingly, however, some human
studies show that inhibition of microglia and cytokines in the brain blunts
such pathological outcomes.”
“Blockade of
inflammation in the periphery and microglial activation/cytokine action in the
CNS, may well become important therapies for a range of disorders not often
thought of as mediated by these factors.”
Conclusion
There is nothing new to me in
the Dana paper; this in itself is rather a shock. If you have followed my blog from the start,
you should also not be surprised; but I
have never seen quite so much scientific good sense written in just four pages. It tells me a lot and reassures me that I am
on the right track with my cytokine blocking therapies, mast cell stabilization and somewhat far fetched, vagus nerve stimmulation ideas.
There are other science-based "inflammation control"
therapies and I will be writing about them later.
P.S. Why no Dean’s List for Martha?
Regular
readers of my blog may have noticed that a small number of the several
hundred researchers, whose papers are discussed here, are given a pat on the
back and moved to the Dean’s List. Why
not Martha?
There is a
good reason. For many years Martha keeps
going on about the “Fever Effect” in autism.
This is the strange phenomenon where autistic behaviours abate during
fever, i.e. sickness associated with high temperature. I myself witness this every time Monty, aged
10 with ASD, has a high temperature. I
think that conclusively solving this, might indeed tell us something profound
about this wide phenotype of autism.
I think with
the resources of Harvard, she should be able to figure this out. Her TRANSCEND Program gives her a pool of
research subjects.
Peter has just one mouse model of autism and,
at the age of 10, he is getting a big to be called a mouse.
So Martha,
put aside the MRIs and the calcium channelopathies, if you figure it out before
me, you get on the Dean’s List.
If I can
prove the underlying reason, I will put myself on the Dean’s List.
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