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.