
Proteins central to the pathology of Alzheimer’s disease act as prions – study - jacques_chester
https://www.ucsf.edu/news/2019/05/414326/alzheimers-disease-double-prion-disorder-study-shows
======
cjbprime
Y'all, please never post _university press releases about single scientific
studies_. They are the worst thing. Every major human problem has been
declared solved by one of them. They are even worse than posting single
scientific study papers themselves at the time of publication, and that's
still pretty bad, because of the overwhelming incentive to create exciting
studies that are wrong, and our current inability to notice the same due to
limitations of peer review in catching results that were created by some form
of chance.

This result looks very exciting and if it replicates and is built upon in five
years' time then we can all talk about it then, you know?

I note that Science Translational Medicine's impact factor is not awesome. But
even that doesn't mean much to me: lately it feels like _Science_ and _Nature_
are in fact _especially_ likely to collect results that are very exciting and
also wrong, because they feel like they're the best journals so their results
should be surprising.

~~~
thaumasiotes
> lately it feels like _Science_ and _Nature_ are in fact especially likely to
> collect results that are very exciting and also wrong, because they feel
> like they're the best journals so their results should be surprising.

I believe this is accurate on all counts.

Slate Star Codex put the issue fairly pithily: there's only one way to get
surprising-if-true results that isn't surprising.

~~~
steve19
Can you explain the joke?

~~~
outlace
The only way to get a surprising-if-true result that is not surprising is if
the result is not true. Hence the joke is that most of these surprising
findings are probably B.S.

------
outlace
Taken out of context, the press release makes this finding look a lot more
ground-breaking than it is after I quickly read through the actual study.
Still a good piece of work though.

It was already known, as pointed out in the actual paper, that Amyloid-beta
(AB) and Tau, the proteins that have long been implicated in Alzheimer's
disease (AD), have prion-like properties which means they exist in an abnormal
3D configuration that causes other AB/tau proteins they interact with to adopt
this abnormal configuration.

But they can also polymerize into large neurofibrillary tangles (NFTs).
Patients who died late, e.g. at age 80 with AD had a lot of these NFTs, so it
seemed reasonable by many to assume that these NFTs are the major cause of
brain deterioration. But there were a number of alternative hypotheses of what
exactly AB and tau were doing in the disease.

This study suggests that AB and tau cause disease primarily through their
prion-like activity and not due to their ability to accumulate into large
trash-balls (NFTs). They noted that patients who died young of AD had very few
NFTs but have a lot of the AB/tau prion-like forms, whereas patients who
survived longer had a lot of NFTs but not a lot of prion activity. This lends
evidence to the idea that the primary pathogenicity of AB/tau is through their
prion activity and not the fact that they accumulate into large protein blobs.

~~~
autokad
could that be interpreted as the ones with trash balls (NFTs) might actually
be the ones handling it 'better'?

~~~
outlace
You mean like the NFTs are somehow protective against the Prion forms? That is
a possible interpretation that this study does not directly disambiguate.

------
netwanderer3
Is it possible that these prions were also acquired by human through meat
consumption? As in the case with PrP prion from Mad Cow Disease which spread
through meat eating as well. Another very similar case is by eating fruit bats
containing toxic BMAA, which has a very similar structure to L-Serine amino
acid causing it to be picked up instead during the protein synthesis process
and resulting in a misfolded version. Studies are being done as BMAA could be
a likely cause for many neurological disorders such as Parkinson's.

Has there ever been any researches in determining the rates of Alzheimer
disease in meat eaters vs. vegetarians?

~~~
stareatgoats
Interesting topic. Here is an anecdote that I found through a simple web
search that somewhat addresses your question:

"Few studies have looked carefully at the risk of dementia in vegetarians
versus other people, and the data is contradictory. One small study of
California residents found that meat eaters were more likely to become
demented than their vegetarian counterparts. Another study in Alzheimer’s
patients, however, found that adhering to a strict vegetarian diet resulted in
lower cognition compared to a pescatarian diet (i.e., a diet that includes
fish)."

[https://www.alzdiscovery.org/cognitive-
vitality/blog/vegetar...](https://www.alzdiscovery.org/cognitive-
vitality/blog/vegetarian-and-vegan-diets-for-brain-health)

~~~
netwanderer3
You're right, I used to know a few vegetarians who often supplement their
diets with Vitamin B-12 which theoretically could help boosting and balance
their cognitive ability vs. meat eaters. I personally did not notice any
cognitive problems in those people at least.

Our DNA contains the sequence of folding steps instruction for each protein to
fold. So for a protein to misfold itself, could this mean it must have
received an incorrect instruction from the source? As we know, damages to DNA
are often a result of foreign agents or coming from external environmental
factors. Prevention is always better than a cure so it is probably a lot
easier to figure out the source and eliminate that rather than trying to
change the structure of these molecules which is extremely difficult.

~~~
fjfaase
As I understand it, the DNA only contains the sequence of amino-acids from
which the protein is built, not their folding instructions. Some proteins are
also modified and/or cut in pieces by other proteins before reaching a
functional state. Discovering how a protein folds, is a very complex problem,
that would have been much easier if it were indeed encoded by the DNA. the
website [https://fold.it/portal/](https://fold.it/portal/) gives a good
introduction to the problem of protein folding.

~~~
achenatx
My biochemistry education is 20 years old.. As you say DNA encodes the
sequence of amino acids. Protein folding is a thermodynamic problem as parts
of the protein stick to other parts and bonds try to achieve a low energy
shape.

There are enzymes, co-enzymes, and other molecules that can help a protein to
achieve its proper shape.

------
breck
A good primer on prions: [http://www.prionalliance.org/2013/11/26/what-are-
prions/](http://www.prionalliance.org/2013/11/26/what-are-prions/)

------
amyloid_tau
Pretty awesome work. Looks like we don’t have obvious ways to avoid these
classes of proteins in the same way we can just avoid tainted meat and abstain
from cannibalism...

[https://en.wikipedia.org/wiki/Amyloid](https://en.wikipedia.org/wiki/Amyloid)

[https://en.wikipedia.org/wiki/Tau_protein](https://en.wikipedia.org/wiki/Tau_protein)

~~~
bboygravity
Or do we?

People taking acyclovir regularly (to suppress HSV1 and 2 symptoms) have been
found to have a 10 fold decrease in risk of getting Alzheimer's (Taiwanese
study).

[https://www.medicalnewstoday.com/articles/322463.php](https://www.medicalnewstoday.com/articles/322463.php)

Additional studies are currently ongoing to confirm this in the US.

The scientific "journalists" seem to jump to the conclusion that therefor
HSV1,2 must be cuasal for Alzheimer's. But it could be that Acyclovir somehow
prevents or slows the formation of AB tau prion-like forms (and has nothing to
do with the herpes - Alzheimer's causality).

Or. Some Acyclovir prevents Alzheimer's through a completely different
mechanism we don't know about yet.

My point: effective medication may already be there. We just don't know how it
works yet.

~~~
Cosi1125
Or, you know, it might be that Alzheimer's has an autoimmune factor
contributing to it... :-)

~~~
bboygravity
Can you elaborate? As far as I know the immunesystem "has no access" to the
brain?

Also by "factor" do you mean protein?

I'm just an electronics guy, would love to know more.

~~~
Cosi1125
Sure! It'a common misconception that the brain is completely separated from
the immune system. If it were, it would take one evolutionarily successful
pathogen to threaten the existence of our species. The brain is indeed
(usually) impenetrable to immune cells circulating in the blood stream, but
there are "resident" immune cells protecting it from everything that manages
to pass all the other barriers. You can read more about it on Wikipedia [1].

By "factor" I didn't mean a biological entity, but rather... well, a factor
contributing to the development of the disease. (As you might have noticed,
English is not my native tongue, and I couldn't come up with a sophisticated
synonym to "a thing that makes a contribution to sth" ;-))

It's been long postulated that AB/tau proteins are only a symptom of
Alzheimer's and not a causative agent (which would explain why, so far, no
treatment has been successful despite pre-clinical successes). According to
some hypotheses, what we observe is the effect of "strayed" lymphocytes going
postal and attacking brain cells after being activated by a microbial agent –
and HSV is one of the suspects.

Hope that helps. If something is not clear, feel free to ask and I'll try to
explain :-)

[1]
[https://en.m.wikipedia.org/wiki/Neuroinflammation](https://en.m.wikipedia.org/wiki/Neuroinflammation)

------
outlace
The actual study is here: "Aβ and tau prion-like activities decline with
longevity in the Alzheimer’s disease human brain" <
[https://stm.sciencemag.org/content/11/490/eaat8462](https://stm.sciencemag.org/content/11/490/eaat8462)
>

------
i_feel_great
I still remember undergraduate biology class where the lecturer mentioned that
crazy idea of proteins being infectious. Most scientist thought the results
were errors and that Prusiner was a fool. Even after kuru was proven to be
cause by infectious proteins.

------
jmpman
How does this mesh with the gingivitis correlation?

~~~
robbiep
There is an inflammatory correlation as well, it may be simply that.

I have been out of the AD literature for about 6 years but back in Med school
read every major paper from the 80s onwards. The flip flop between tau and AB
as the causative agent was very interesting

------
jeffdavis
How does a protein come to be misfolded? Is it a random mutation that happens
to be self-propagating? Is it different between alzheimers and other ones like
mad cow?

~~~
robbiep
Thermodynamics.

Certain proteins have a propensity to Misfold, this is driven by the folding
conformations as well as by Heat Shock Proteins. The underlying genetics that
drive amino acid sequence are the basis for this. In the best known prion
disease, Mad Cow, one misfolded protein drives other similar proteins it runs
into to induce the same conformation. Due to the thermodynamics of folding, it
is now in a very stable structure and won’t revert to its original or desired
biological structure, is difficult or impossible to clear, and will cause
other proteins to fold in the same way.

~~~
jeffdavis
So the first misfolded protein is just a random occurrence?

With mad cow, will uninfected cow populations spontaneously develop mad cow on
their own? Or was the first mad cow protein a rare misfortune not likely to
happen again? Or did the first mad cow protein come from something other than
a cow?

~~~
robbiep
Look up the sheep prion disease scrapie. It’s been around a lot longer than
mad cow (1700s) and likely continues to arise spontaneously.

The protein structure needs to have a mutation which gives it a propensity to
occasionally misfold. That creates a chain reaction. If this happens at a low
enough rate then the underlying protein may become widely distributed in the
population, and then it may only take a chance mutation or misfold to cause
the cascade

The reality is we don’t know what the prime mover in any of these conditions
are. Likely some combination of random occurance and possibly some other
mechanism as well. For example, CJD comes from mad cow - so mad cow is
transmissible, but scrapie seems to both arise spontaneously in flocks and be
transmissible between sheep

------
pretendscholar
Can someone with a better background tell me if this is a game changer? I
thought the consensus was that Alzheimer's probably had a few potential
causes.

~~~
icegreentea2
There's nothing in principle that prevents other mechanisms from inducing the
prion conditions that eventually leads to Alzheimer's symptoms.

This paper is just another piece of evidence that points to the plaques and
tangles being self propagating, instead of being say for example a pure by-
product of some other mechanism. In itself, that doesn't really tell us
anything about the mechanisms at play.

Is it a game changer? Probably not. It's unlikely that Alzheimer's is purely
spread through inter-human prion transmission, so other factors are likely
still at play.

------
viraptor
Are there any curable prion diseases right now? As far as I can tell from
googling, CJD does not have any known cure. If there aren't, does it mean we
need to come up with a completely new class of treatments?

~~~
telchar
Speculatively, in the future we may be able to design proteins that would
target the prions and destroy them or refold them into less harmful shapes. To
do that we would need to 1. know what protein shape would be required and 2.
be able to figure out how to make that shape (what sequence would happen to
fold itself into that shape). I would think we would need to advance quite a
bit more in protein science before that is feasible.

~~~
echelon
Just to provide background, what you describe is nowhere close to feasible.
Designing novel proteins is computationally intractable. It took evolution
billions of years and parallel optimization to figure out how to problem solve
with polypeptides. We're not even at the punch card phase.

~~~
resiros
That is simply not true, we have been making great progress in protein design
in the last years. I recommend you take a look at this Nature review by Baker
one of the biggest names in the field:

[https://www.nature.com/articles/nature19946.pdf?origin=ppub](https://www.nature.com/articles/nature19946.pdf?origin=ppub)

------
dreamcompiler
This is an absolutely astonishing game-changer for Alzheimer's research. The
scientist who discovered prions (and got a Nobel prize for it) now has
convincing evidence that the proteins that cause Alzheimer's are themselves
prions. Amazing, scary, and hopeful all at the same time.

~~~
thanatropism
Well, when you’re an authority on prions everything looks like a prion
disease.

~~~
labster
As a web developer, I'm curious if Alzheimer's is really a cross-site
scripting attack. If so, we could prevent it by encoding the amino entities,
and that would be a game changer.

~~~
JoeSamoa
The encoding would have to be part of our DNA though right? Do you think this
method would work as a treatment or just as a method of prevention?

I like your mindset and I think your metaphor may be correct.

------
josephagoss
Does this mean that inflammation of the brain is to be ruled out as a cause?

~~~
thaumasiotes
cheesymuffin's comment is downvoted, but I think he's on to something. It
would be very odd to consider inflammation of the brain to be a _cause_ of any
problem, because inflammation is a symptom of something else.

~~~
wahern
Inflammation often is directly causative, for example atherosclerosis where
the inflammatory response directly results in the buildup of plaques.
Inflammation is not typically the _root_ cause, however; something else
instigates the inflammation.

The distinction matters because the best treatment (greatest efficacy, most
cost efficient) may target one or more of the links in the causative chain,
but not necessarily the root cause.

~~~
thaumasiotes
Fair enough. Treatment can attack any link in the chain.

Prevention can't, and to me Alzheimer's is something that should be prevented.
But we work with what we have.

------
Jasmine_Hubbard
This makes the disease even worse than expected and it's already a wicked
disease. Has a prion disease ever been treated?

------
Haga
The problem is too little capitalism in science. Hear me out on this one
please. We humans have a natural fear of breaking up into small groups and
parallel execute counterrunning endavours.

------
hansflying
Bad news! Prions are extremely stable and not even boiling, Protease or high
radiation can disrupt them.

~~~
londons_explore
_Some_ prions are extremely stable

