Growth or No Growth: APP Weighs the Question
Angela Biggs Proposes a Biological Function for APP
First, consider the two forms of APP. The membrane AβPP form has a
receptor-like protease(1) with a cytoplasmic region capable of binding
small G-proteins.(2) In neurons, the membrane form is found at the
synaptic zone at the tip of growth.(3,4) The secreted form of APP is an
extracellular protease that has been shown to stimulate neurite
extension.
Now consider that AβPP is also known as protease nexin II, a
serine protease.(5,6,7) The serine protease inhibitor neuroserpin has
been shown in PC12 cells not only to decrease the length of neural axon
extensions, but also to stop axon growth altogether.(11)
I propose that the biological function of APP appears to be to
act as a serine protease to "switch" neurons into the growth mode.
To weigh this idea, discoveries in other cell types should be
considered: Maspins are serine protease inhibitors that insert into the
membrane and control the cytoskeleton; without maspins, breast cancer
cells metastasize.(8)
Next, consider that P53 turns on maspin expression by binding
DNA.(9) Note that p53 binding is also required for bcl-2 expression. In
neurons, AβPP seems to prevent p53 from binding to DNA.(10) So serpins
and serine proteases have opposite relationships with P53. This makes
sense because p53 binding protects quiescent neurons from apoptosis via
bcl-2, while rapidly growing neurons could be easily eliminated if
needed.(14)
Neuroserpins and α-1-antichymotrypsin (α-1-ACT) are serine
protease inhibitors that could be acting as maspins. Interestingly,
expression of APP and α-1-ACT have been shown to coexist together in the
membrane of human skeletal muscle.(12)—a serine protease receptor with a
serine protease inhibitor receptor.
Putting it all together, there seem to be two critical states of
neurons: those that are growing and using serine proteases to do so, and
those that are quiescent. Growing neurons would be using APP pathways,
possibly through RhoG (a small G-protein) to extend microtubules,
whereas quiescent neurons would use the membrane serpin. I speculate
that serpins may act through RhoA to dictate a non-growth cytoskeletal
structure.(13)
APP and Cholesterol
Another nice feature of this proposed APP function as a
controller of "growth of non-growth" is that it explains the cholesterol
relationship. The elongated membrane of the nerve growth cone would
require more cholesterol in the membrane for structural stability.
Simple membrane structures require less cholesterol, while complex
membrane structures require more. The addition of cholesterol to
membranes stabilizes the lipids, thus preventing them from floating
away.(15) If the body wanted to get rid of cholesterol, it might attempt
to use as much as possible in complex membranes like those of growing
axons and growth cones.
For example, treating APP-transfected HEK cells with statin drugs
reduced the processing of newly synthesized APP. Adding cholesterol to
the HEK cells increased BACE cleavage of APP by fourfold.(16) The cells
appear to choose the APP pathway in order to use cholesterol in the
membrane!
What about the decrease of the α-secretase processing of APP? My
understanding is that there are two main types of APP cleavage, α and β.
Transgenic mice overexpressing APP when exposed to high cholesterol
show an increase of the β-secretase cleavage of APP and a decrease of
α-secretase cleavage.(17) Since α-secretase cleavage occurs at the
membrane surface of neurons,(18) I suggest that this α cleavage might be
an "off cleavage." Could it also be that neuroserpin inhibits APP, then
the secretase cleaves it, turning the growth mode of the APP receptor
off permanently, then stimulating the nerves nearby as if to take turns
growing?
I reason that high cholesterol would push neurons into the APP
cytoskeleton growing mode, which uses cholesterol in the membrane.
Problems could occur once the neuron could no longer keep up the growing
pace, or too much Aβ was made due to high cholesterol stimulating APP
production. If the nerve became stuck in the growth mode, it makes sense
that proteins used in growth could pile up; this includes APP, tau,(21)
and α-synuclein as a plasma membrane omega fatty acid transporter.(22)
APP and Dementia
Another appealing feature of APP functioning as a serine protease
and the neuron switching into a growth mode is that it might also help
explain dementia and the neuron's mitochondria. Assuming that the
mitochondria must be coordinated with neuron growth and division, it is
interesting to note that the transmembrane protease called rhomboid
responsible for the proteolysis of mitochondrial membranes is a serine
protease.(19) So a serine protease in mitochondrial membranes appears to
remodel the mitochondria from the mesh system into "portable,
hotdog-like" organelles. I am suggesting that when APP, a plasma
membrane serine protease receptor, switches the neuron to a growth mode,
somehow a serine protease in the mitochondrial membrane is also
switched on.
Where does this line of thought lead? Mitochondria have been
called the "memory" of neurons, as they use their calcium stores to
record stimulation and adjust neurotransmitter release based on
stimulation.(20) Wouldn't it be interesting if the morphology of the
mitochondria affected this calcium memory property? For instance, if the
mitochondria are in the mesh form, the neuron can "remember," but when
mitochondria are in the hot dog form during serine protease expression,
the neuron cannot. This is, in effect, a speculation that sudden
returnable memory relates to the state of the mitochondria. It is
unknown whether the APP serine protease in the plasma membrane is
coordinated with the mitochondrial serine protease, but the fact that
they are both transmembrane serine proteases is suggestive. Could APP
trigger dementia by causing the mitochondrial serine protease to be
expressed?
Consider resveratrol, the polyphenolic compound of red wine,
cranberries, and blueberries. Resveratrol has been found to slow the
growth of prostate cancer cells.(23) Serine protease inhibitors—the
serpins—use their phenol groups to inhibit the serine proteases. Could
the return of memory that occurs with blueberries and other
resveratrol-containing foods actually be due to resveratrol acting like a
serpin, thus inhibiting the serine protease of the mitochondria and
allowing the mitochondria to form back into a mesh?
There are a lot of possibilities with this growth model of APP as
a serine protease. I hope enterprising scientists will take up testing
it! —Angela Biggs, Independent Researcher.
Please note: Just in case it is not mentioned in the
live discussion, I would like
to note that clioquinol is an antifungal and it is not entirely
understood how it is working in Alzheimer's patients.
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