Proteins central to the pathology of Alzheimer’s disease act as prions – study | Hacker News Reader

Proteins central to the pathology of Alzheimer’s disease act as prions – study

ucsf.edu

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.

> 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.

Can you explain the joke?

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.

Here's how I explain it: Science and Nature play a role different from other journals. Their role is to stimulate new thoughts amongst the most skilled in the field. Any really good scientist in a field can read a paper published by another really good scientist and hone away the bullshit, but be inspired by the ideas. People who are not skilled in the art of reading a competitive paper are going to be disappointed by the sloppy lab work, sloppy writing, sloppy thinking, because it appears that the overall benefit of disseminating new ideas widely for experts to cogitate on may exceed the value from having "perfectly correct" papers.

Case in point: the original DNA structure paper (W&C, 1953) actually had a wrong detailed structure for the DNA (but the right conclusion about how the structure provided a hypothesis for a templating mechanism) because the alcohol concentration used to form the crystal was too high. The value of getting the paper out the community ASAP greatly exceeded the small details that were wrong (which eventually got resolved), because it stimulated the thought of the community around the templating mechanism.

Obligatory: http://languagelog.ldc.upenn.edu/myl/ScienceNewsCycle.gif

one of the authors discovered prions, so I am not so quick to discount their work.

that's an argument from authority rather than one of science though.

we believe things only once we've exhausted our attempts to disprove it

Parent is right this is an appeal to authority. It doesn’t make it more or less right whether a Nobel prize winner comes up with the idea or my mom does, we need to evaluate it on its merits alone. The corollary as I mentioned in a sibling post is that when you have a hammer everything starts to look like a nail.

We rely on a million appeals to authority every day of our lives. Try some new food, trusting that it won’t kill you because somebody says it won’t, and nobody bats an eye. Say you give more weight to a study performed by an expert, when that has no immediate bearing on your life, and everybody loses their mind.

Well said. Myself specifically, I'd like to think science is supposed to be better than that -- neutral, dispassionate. It probably isn't because it's done be humans, but I want it to be.

The people studying this stuff definitely need to be better than that. They can maybe take hints from authorities but they need to check facts for themselves.

But for the rest of us, we have no choice but to trust authorities in some way when deciding how to interpret some new result.

I have to strenously disagree on this point. In this case, the author won the Nobel Prize after fighting the establishment for 20 years over a basic idea- that a disease could be caused by misfolded proteins and that the proteins can themselves cause more proteins to misfold in a cascade- ultimately showing that his theories were correct.

When a person fights the establishment and shows their data and ultimately gets accepted and defines the new paradigm, they've earned a seat at the table to speculate on how things work. They proved their worthiness as an authority.

That doesn't mean we shouldn't evaluate on the merits, but the priors are very heavily in his favor.

> that's an argument from authority rather than one of science though.

No. An appeal to authority would be "this must be true because someone authoritative said it". Saying "I am willing to treat this claim more credibly than other claims because the source is credible" is not a logical fallacy.

It's a Hacker News favorite to point out logical fallacies in comments as if that automatically refutes them.

>"I am willing to treat this claim more credibly"

That's a personal heuristic - a very reasonable one, but it's still an argument from authority.

A heuristic is a bias, not a fallacy. "All else equal, I'll try this path first".

A fallacy assumes a cogent argument is being made. This is just a preference.

Assigning any credibility to a statement based on the identity of its source is indeed the logical fallacy known as "appeal to authority".

Whether you say "it must be true", or "it is likely to be true" does not matter. Credibility must only come from the statement itself and the evidence to support it.

However, while it is a logical fallacy, it is reasonable to temporarily hold beliefs for or against the truthfulness of a statement while no or insufficient evidence is present. As long as belief is not mistaken for proof, nothing is wrong about having such gut-feeling.

There’s nothing fallacious about assigning greater probability to a claim made by a relevant authority. Such claims are actually more likely to be true.

> Assigning any credibility to a statement based on the identity of its source is indeed the logical fallacy known as "appeal to authority"

I think you are confusing deductive and inductive reasoning.

This fallacy is usually taught as appeal to irrelevant authority. It concerns relying on those who purport to be experts but lack any actual expertise.

"The ad verecundiam fallacy concerns appeals to authority or expertise. Fundamentally, the fallacy involves accepting as evidence for a proposition the pronouncement of someone who is taken to be an authority but is not really an authority."

Stanford Encyclopedia of Philosophy (9): https://plato.stanford.edu/entries/fallacies/

Here we have a researcher who is an expert in the thing he's talking about. There are still absolutely reasons to be guarded-- the matter is not fully decided, it's just one study. Maybe this is an example of an ongoing controversy, and we're selectively ignoring other experts?

But it is different to extend a cautious benefit of the doubt here than it would be to take, say, Paul Rudd's word on the topic as final.

The important context here is that the author spent 20 years fighting The Establishment over the facts of prions and ultimately was proved completely correct. that makes him the ultimate authority in this case because he had to actually fight to overturn a long-standing scientific belief with heroic data collection and a hostile environment

Prusiner actually proved his case well over a decade before the establishment was ready to accept his findings. They literally denied his results were true and accurate. Accepting that proteins can catalyze misfolding in a cascade was not an easy thing for the establishment to accept (however, by the time I attended UCSF, prusiner's work was already being suggested to be valid, and people were already working on mechanism).

If the author discovered prions, wouldn't this make him strongly biased toward thinking that prions are the key to solving important problems?

Sure, but this particular study came out of the lab of the Nobel-prize-winning scientist who literally discovered prions. I think it's at least worthy of discussion.

Prusiner has been on the path to this study for quite a while, at least since a talk of his I attended in 2011.

He was on that path in 1999 when I skipped a day of high school to attend a lecture he gave. (I also later became a prion researcher, specifically in a lab that worked with Alzheimer's).

You know what they say, when you’ve got a hammer everything looks like a nail. I’m an armchair physician at best, and I’d say that this doesn’t disprove the viral infection thesis at all. That amyloid and tau act as prions isn’t really relevant if they’re in fact produced initially in response to an infectious agent in an attempt to stop its spread. I’d suggest this is particularly likely to be true as attempts to clear out or suppress the amyloid and tau plaques in fact clear them out with no impact on cognition. This is mentioned in the article itself.

plaques are proxies of disease, not disease-causing or necessarily harmful in themselves.

Pardon me if I misread, it seemed that the thesis here was Amyloid and Tau 'prion' self-propagation was being identified as a cause of Alzheimers.

> Y'all

Instant throwback to 1997's Redneck Rampage game about US hillbillys..

Can you please not post unsubstantive comments to Hacker News?

The worst part is that while articles about a disease like this are a mere annoyance to us, for people with loved ones with the disease or suffering from the disease itself it becomes a cruel joke.

These are people who scour the internet looking for any information they can find and carefully read articles like this looking for a bit of hope that there may be a solution. But it’s bullshit. Don’t share these articles, for their sake.

Totally agree.

I'm the OP.

I do not have, but I am personally affected, by this disease.

I appreciate your point, but this is one of the more interesting alternative hypotheses I've seen in the past ~8 years as an unwillingly-interested layperson.

senior author of the article was the person who established that prions are a legitimate disease caused by protein folding he had to fight an uphill battle for over 20 years to get his ideas established so I'm going to actually give him a ton of credit and the ability to publish what he wants to because he's already demonstrated he's responsible. He also won the Nobel prize for that work.

You could modify your belief in his authority based on the fact that this result was presumably rejected by top-tier journals, and probably for non-trivial reasons. I don't know anything about the field so I can't say whether that's appropriate here. But if you're willing to grant credence based on a prior Nobel, you should be willing to consider taking some away based on the publishing journal's reputation. Why wouldn't a top-tier journal want to publish a Nobel winner's Alzheimer's breakthrough?

Where did you get the idea his work was rejected? Also, his work was rejected by top journals for decades until people finally realized he was correct.

If it could have been published in Science, then it wouldn't have been submitted to Science Translational Medicine, a completely different journal with much less visibility (and a much lower impact factor). For some of these Nobel guys you could argue they want to avoid supporting the flashy magazines and don't care about getting into the high impact journals because they are already established, but in this case he actually submitted to a Science-family journal, so he's very unlikely to be making some principled stand.

You claim is entirely speculative. There may be good reasons why it didn't show in Science (page space is extremely limited)

Yes, it's speculative. But so is the idea that this work is correct because he won a Nobel in the past. That's the point: you're making guesses based on limited evidence, and we're pointing out that you didn't use all available limited evidence to influence your guess, just some evidence that confirmed what you already felt. This is a kind of bias.

> There may be good reasons why it didn't show in Science (page space is extremely limited)

Um, exactly? Science is the most visible journal after Nature, so it's the most competitive. "Insufficient page space" is exactly the same as "not impressive enough to be accepted".

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.

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

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

Could just be an innocuous buildup with no effects either way, that just results from having the disease a long time. I doubt it's a direct result of handling the disease well but I don't know anything about what defenses our brains have against prions

The big issue that AB/hyperTau studies seem to studiously ignore: studies in human brains have found an inverse correlation between the sites of the brain with excess plaque formation and the sites of the brain with the most significant atrophy and functional decline.

This is unsurprising, given the last two decades of drug trials targeting these molecules have all uniformly failed.

The alternative hypothesis is that these plaques are protective against neuronal infections that provoke alzheimers. That hypothesis has not garnered wide support yet, though it is growing, and is at least consistent with the inverse relationship observed.

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?

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...

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.

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/ gives a good introduction to the problem of protein folding.

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.

For many proteins, the sequence encodes the fold (many small proteins refold spontaneously with just their amino acid sequence). That proteases or other activations may be required to functionalize the protein is irrelevant- the sequence in the DNA causes the protein to fold to its preprotein state reversibly.

A good primer on prions: http://www.prionalliance.org/2013/11/26/what-are-prions/

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/Tau_protein

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

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.

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

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.

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

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 >

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.

How does this mesh with the gingivitis correlation?

I wondered the same.

I suppose there is nothing saying that it can't be both be a prion disease, and enter the brain through a gingivitis path.

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

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?

This is all preliminary, so nobody knows for sure about Alzheimers, but assuming it was, then it would likely be a different protein. (IOW a different linear chain of amino acids, that folded in a non-standard way.)

I have no idea what the mechanisms affecting protein folding are in this context, but if you are interested in learning more about how proteins fold and perhaps helping researchers fold interesting new ones, check out FoldIt (a protein folding citizen science project): https://fold.it/portal/

It was featured in Werner Herzog's Lo and Behold and I had the privilege of taking a class taught by a professor involved in its development. The community there can do a little bit to restore your faith in humanity and technology.

This still exists? I'll have to check it out again sometime...

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.

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?

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

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.

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.

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?

There are no current treatments for Alzheimers that do much of anything. If the problem/cause is more confidently known, at least there is a more narrow target to aim at.

There are no current treatments for Alzheimers that do much of anything.

Well, unless you count physical exercise.

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.

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.

Would quantum computers with more logical qbits help? My layman impression was that this could solve protein folding.

This would be a good use-case for a bitcoin or alt-coin.

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

Could we tag them with the immune system?

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.

To someone with minimal background in biology, prions are a fascinating and terrifying phenomenon right out of speculative fiction. Absolutely amazing and scary.

Prions remind me of ice-nine.

Need to read this!

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

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.

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.

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

What is inflammation?

The immune system kicking into gear.

- vasodilation

- production of cytokines and chemokines

- cell recruitment

- cell proliferation

- upregulation of certain genes

You're kicking your immune system into gear in some shape or form.

Keep in mind the immune system is one of the most complex signalling systems in the body. You can trigger it in different ways and get different responses.

No..

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.

Yeah I agree, however I'd imagine if inflammation was the cause of issues (and I recall some studies showing brain inflammation to be linked to some brain disorders) then perhaps more research would go into what causes the inflammation.

Some evidence the inflammation might be diet related too. Although I can't recall the source at the moment.

Being a symptom doesn't absolve it of being a cause too. If a thousand things can cause inflammation, but then there's a package of symptoms caused by inflammation itself, then it could be worth it to directly fight the inflammation in a lot of cases.

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.

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.

Inflammation is often an immune system response to a foreign agent, and I read somewhere that prions could also be triggered and formed for the same reason so there might actually be a link. I imagine chronic inflammation over a long period of time could do a lot of damage.

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

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.

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

Some prions are extremely stable

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