Friday, 20 December 2013

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:-

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:-

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.

  =  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.

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 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.

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.



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