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We Have Given People Amyloid Disease

Unfortunately, it’s time to talk transmissible protein pathology again. That’s the unnerving idea that misfolded proteins can, under some conditions, act as infectious agents (prions are the most famous examples and the most widely-used name for these). I wrote in 2015 about a particularly alarming possibility. It’s known that up until the 1980s, some patients who had been treated with human-cadaver-isolated growth hormone preparations had also been infected with the prion that causes Creutzfeld-Jacob disease. The 2015 paper saw signs of amyloid pathology as well, and suggested that misfolded amyloid protein had been transmitted, too.

Now the authors appear to have nailed that down. They’ve tracked down archived vials of the growth hormone in England, and they’ve shown that these contain beta-amyloid (both 40 and 42 amino acid length) as well as tau protein. And what’s more, they did experiments with mice expressing humanized APP and mutations that are known to produce amyloid pathology. It’s already known that inoculation with brain homogenate from human Alzheimer’s patients seeds amyloid plaque formation. But inoculation with these old HGH samples is sufficient to induce amyloid pathology as well. The results seem very clear. Animals treated by intracerebral injection with saline or with recombinant growth hormone look just like untreated controls, but every one of the old-growth-hormone treated animals show both plaques out in the neurons and along the vasculature (cerebral amyloid angiopathy).

Our proposal that human transmission of Aβ pathology had occurred as a result of intramuscular injection of c-hGH is now firmly supported by experimental evidence. While the individuals we described in our earlier report did not meet the full neuropathological criteria for Alzheimer’s disease, they might have done so if they had not died of iCJD at a relatively young age.

Coupled with the news that amyloid pathology has been spread through surgical procedures (mentioned in that earlier blog post as well) and with other experiments on spreading amyloid deposits, it seems past time to start being careful about this business.

Although we reiterate that there is no suggestion that Alzheimer’s disease is contagious, and no supportive evidence from epidemiological studies that it is transmissible (notably by blood transfusion), we consider it important to evaluate the risks of iatrogenic transmission of CAA, and potentially of Alzheimer’s disease. Given the lack of disease-modifying therapeutics for Alzheimer’s disease and other distressing and fatal neurodegenerative conditions, it will be important to consider introducing improved methods for removing proteopathic seeds from surgical instruments on a precautionary basis.

That it is. And I’m not sure what those improved methods will look like, considering how resistant some of these protein aggregates can be. But there seems no doubt that under forcing conditions (direct injection of protein or tissue preparations, transmission by surgical procedures, etc.) that these pathologies can be transmitted. This along with the work on alpha-synuclein and other such proteins tells us that we really can be living on the edge when it comes to protein stability. You’d think that the danger would be instability – after all, things fall apart. But there is such a thing as too much stability. Life needs to be flexible and to take advantage of reversible reactions, so thermodynamic sinkholes like these protein aggregates are as deadly as a tar pit.

56 comments on “We Have Given People Amyloid Disease”

  1. luysii says:

    There is a lot of (physical) chemistry to be done on when proteins aggregate. The beautiful stereochemistry of selective enantiomeric photochemical synthesis of a chiral compound from an allene (beloved by organic chemists) will not be involved [ Nature vol. 564 pp. 197 – 199, 240 – 243 ’18 ]. Consider the many liquid protein droplets in the cell (nucleolus, Cajal body, stress granules etc. etc.). They contain ten to hundreds of different protein RNA and DNA components.

    To my knowledge this sort of thing was NOT predicted by any sort of theoretical chemistry. So biology is now beginning to give to chemistry in the same way that string theory (and physics) has begun to give to mathematics.

    For more see — https://luysii.wordpress.com/2018/12/16/bye-bye-stoichiometry/

  2. Sofia says:

    Now comes the follow up study where we randomly assay surgical wards and find out how prominent proteopathic contamination on surgical instrumentation really is.

    1. Gene says:

      My kingdom for an upvote for this comment. I want to see the results of that study.

  3. Tuck says:

    If it’s similar to CJD, that also suggests it may be incurable, unless someone has a bright idea of how to purge the damaged proteins…

    1. Derek Lowe says:

      That’s correct – it is indeed uncurable, at least by anything we know about now.

    2. Simona says:

      There are some promising anti-amyloid and anti-prion drugs being developed now, cf substituted indole-3-glyoxylamides or miridesap

  4. Ted says:

    This…

    so thermodynamic sinkholes like these protein aggregates are as deadly as a tar pit

    …is both an illustrative and imagic analogy, and deserves to be called out as such. Well done!

    -t

  5. Jeff says:

    Chlorine trifluoride autoclaves, anyone?

    1. tlp says:

      don’t forget, you need functional surgical instruments after treatment

    2. Beavis says:

      Dry heat sterilisation of “metal” instruments at 250C. Works nicely for depyogenation.

      1. Falanx says:

        And wrecks the heat treatment of the edge of corrosion resistant steel scalpel blades.

        1. Hunt Bobo, MD says:

          Scalpel blades are all disposable.

    3. Roger Moore says:

      Autoclave in concentrated alkali. You should be able to reduce any protein to individual amino acids.

      1. Falanx says:

        Really, don’t. Corrosion resistant steels hate boiling lye and other things.

        Boiling 10% citric acid on the other hand they’ll happily sit in all day without damage.

  6. bacillus says:

    Here’s the recommendation from the Public Health Agency of Canada for decontaminating reusable labware contaminated with prions:

    For reusable instruments that are not heat-sensitive: Autoclaving at 134°C for 1 hour (i.e., single-step decontamination process) or a chemical treatment with 1N NaOH or NaOCl followed by autoclaving at 121°C for 1 hour (i.e., two-step process) is acceptable for prion decontamination.

    1. Nile says:

      Pathologists who perform autopsies on suspected CJD fatalities would disagree.

      The instruments are lethally dangerous no matter what you do, and you keep the CJD table and it’s equipment separate, for use only with full-coverage protective suits with an air supply.

  7. MrXYZ says:

    There is always a lot of discussion on this blog on whether depletion of Abeta is a reasonable approach to treating Alzheimers and, in fact, whether the amyloid hypothesis is valid at all for AD.

    Does this work change anyone’s viewpoint?

    1. John Wayne says:

      The ‘real’ cause (or causes) of diseases like Alzheimer’s will almost certainly explain the observations between amyloid and phenotype. That association is real, the question remains how important it is.

    2. Ian Malone says:

      Well, I’m normally on the “Aβ plays some causative role” team, but to swap jerseys for a moment, if you believe there’s some other infectious vector involved, then the presence of amyloid in the donor samples merely indicates they had it and it could also be present in these samples. Still to answer the question of why some people can have plaques and not develop clinical AD, differing susceptibility is a possibility, these mouse models are chosen to be prone to plaques and amyloid angiopathy.

      1. Lane Simonian says:

        I will limit my comments to the prion disease and not the Alzheimer’s disease side starting with this article:

        Accumulation of prion protein in the brain that is not associated with transmissible disease

        These data suggest the possible isolation of an infectious agent that promotes PrP amyloidogenesis in the absence of a spongiform encephalopathy. Alternatively, the infectious agent may be rendered nonpathogenic by sequestration in amyloid plaques, or PrP amyloid can seed amyloid accumulation in the brain, causing a proteinopathy that is
        unrelated to prion disease. Formation of PrP amyloid may therefore not necessarily be a reliable marker of transmissible spongiform encephalopathy infectivity.

        Amyloid plaques may either entomb the infectious agent itself or entomb copper which may be one of the contributors to prion diseases.

        https://www.sciencedaily.com/releases/2012/08/120809190725.htm

        There is a difference between an infectious agent directly causing a disease (such as prion diseases) and an infectious agent being a potential factor in a disease.

        1. Lane Simonian says:

          Further evidence that amyloid plaques are protective against prion diseases and certain other neurodegenerative diseases.

          “Nitration of amyloid-β peptide (1–42) as a protective mechanism for the amyloid-β peptide (1–42) against copper ion toxicity”

          The problem likely is that the plaques do not form soon enough.

  8. sgcox says:

    “But Collinge’s team was able to locate old batches of the growth-hormone preparation stored as powder for decades at room temperature in laboratories at Porton Down, a national public-health research complex in southern England.”

    Hmm, that is where Novichok was identified.
    Interesting place…

    1. Derek Lowe says:

      Would you like to elaborate, or are you just going to leave that dangling out there?

      1. Calvin says:

        Not quite. There are two sites there, one run by PHE and the other which could be best described as a Military facility (it’s called DSTL). They are separate. Separate fences etc. The PHE part has a certain academic/government feel and while happy to deal with Ebola etc does not have an onerous feeling. DSTL, the military part, is a different matter and you are aware you are always accompanied and being followed/watched. So these samples came from the PHE part which would not raise eyebrows quite as much had they come from DSTL

      2. sgcox says:

        What is wrong with a good conspiracy story for the next Bond movie?

        From the same Nature comments: “Britain stopped the cadaver-derived growth hormone treatment in 1985 and replaced it with a treatment that uses synthetic growth hormone. ”

        By that time… Leonid Brezhenev died in 1982 of unspecified causes but clearly displaying all obvious signs of Neuro degeneration, then Yuri Andropov died in 1984 because of kidney failure – surely kidney amyloidosis , then Konstantin Chernrnko of totally bad health in 1985 (lets leave it unspecified).
        and apparently from President diary:

        “The significance of Chernenko’s death was lost on the 40th president. Reagan’s diary entry for March 11, 1985 simply noted that he was woken at 4 AM and told of Chernenko’s death. In the days that followed, Reagan, in his own words, “decided not to waste any time in trying to get to know the new Soviet leader.” Perhaps more than anything, Chernenko’s death frustrated the 40th president.

        “How am I supposed to get anyplace with the Russians if they keep dying on me,” he asked his wife upon hearing the news.”

        Then of course the young and energetic Michael Gorbachev came to power, destroyer Soviet Union and delivered his end of the bargain. Porton Down went silent…

        How agents delivered intracranially to the top Politburo members is up to scenarists.

        Much better than practically any conspiracy stories so far!
        May be I should copyright it.

        1. Druid says:

          Porton Down does hold unexploded gas shells and cannisters from World War 1 found in the fields of Belgium and France, until they can get around to disposing of them safely (one at a time!) in an elaborate containment system. Another reason for tight security, though it was the subject of a very rare occasion when a film crew was allowed in to the site to watch the destruction at very high temperature. Good work.

        2. RxL says:

          I would love to watch that movie/read that book!

          1. Druid says:

            The BBC seems to show it twice a year and maybe soon. Dr Michael Mosley investigates.

  9. Anon says:

    Must be that prroxynitrites are trapped on the surgical instruments somewhere.

    1. Lane Simonian says:

      Or the pathogen that causes the formation of such:

      “Choline acetyltransferase (ChAT) and choline transport are decreased after nitrosative stress. ChAT activity is altered in scrapie-infected neurons, where oxidative stress develops. Cellular prion protein (PrPc) may play a neuroprotective function in participating in the redox control of neuronal environment and regulation of copper metabolism, a role impaired when PrPc is transformed into PrPSc in prion pathologies.”

      “Evidence for oxidative stress in experimental prion disease”

      Oxidative stress has been shown to be important in several neurodegenerative disorders. Previous in vitro studies have already demonstrated the ability of a prion protein fragment to induce oxidative stress in cultured cells. By immunohistochemistry for nitrotyrosine (NT) and heme oxygenase-1 as markers for oxidative stress, we found widespread neuronal labeling for NT in scrapie-infected mouse brains, in agreement with peroxynitrite mediated neuronal degeneration. Damage by free radicals is a likely cause for neurodegeneration in prion disease, and antioxidants are a potential therapy of these disorders.

  10. sgcox says:

    Well, it is interesting place 🙂
    And no, they did not make Novichok, it came from Russia. They just have fantastic analytical facilities.

    1. loupgarous says:

      Riches, Timperley. et al at Porton Down also identified the specific fentanyl derivatives (carfentanil and remifentanil) used by Russian special forces troops at the Barricade Theater in Moscow on the terrorists which occupied it and their hostages.

      To do so, the Porton Down team synthesized their own lab standards of fentanyl hydrochloride, cis-3-methylfentanyl free base, carfentanil oxalate, sufentanil citrate, lofentanil oxalate, remifentanil hydrochloride, norcarfentanil and remifentanil, then verified the lab standards’ purity by NMR spectroscopy, and then analyzed material recovered from the clothing of returned British hostages, and urine from one of the hostages.

      It’s safe to say that these guys not only have fantastic analytical facilities, but take thoroughness to the next level.

    2. Crocodile Chuck says:

      “And no, they did not make Novichok, it came from Russia’

      How would you know?

    3. fajensen says:

      I’d consider it their “damn job” to synthesize terrible things like Novichok. Since these awful materials exists, then as part of our defence against them, we have to know how they work, what treatment there is, and how to detect them, in whatever circumstance one would expect to meet them.

      How would we know if “it came from Russia” if the experts have not already acquired and characterised the (likely) many different variants of the material and ways of making it?

      Attribution is important work with serious real world consequences. It is not enough to base these decisions only on the words of politicians!

  11. Yvar says:

    Working on a project where we’ve made a piece of a luciferase that we can detect at zeptomole level, it is amazing how truly difficult it is to get that peptide out of equipment/tubing once it has been in there even one time. Decontamination procedures certainly reduce the levels dramatically, but that isn’t the same as gone. Makes me really wish we knew that there was a known lower concentration limit for amyloid infectivity, but I’m not aware of one…

    1. a. nonymaus says:

      Given the exposure of the CNS via the olfactory bulb, I’m now wondering how much A-beta or its aggregates is shed in inhaleable aerosols as a component of nasal mucous. And, for that matter, whether amyloid inhalation is pathogenic.

      1. loupgarous says:

        The late Carleton Gajdusek (who won the Nobel for discovering the causative agent of kuru, which turned out later to probably be a prion – or, depending on other people than Stanley Prusiner who’ve studied the slow encephalopathies, a “slow virus” or another transmissible agent) described an experiment to Richard Rhodes (author of Deadly Feasts: The “Prion” Controversy and the Public’s Health) in which terminal patients volunteered to sniff fine gold dust after having their sinuses dried out with atropine. Later autopsies revealed the gold dust was carried to the hippocampus by reverse axonal transport.

        It’s probably time for studies of how readily amyloid and other things associated with AD and other slow encephalopathies are taken up through the nose into the brain.

        1. Thoryke, being facetious says:

          Well, if we’re going _there_, why not find out how much of the gut microbiome gets excreted, aerosolized by modern toilet flushes, and inhaled/swallowed by other people, thereby implicating lavatory facilities in the ‘transmission’ of obesity…?

  12. Barry says:

    If I were to channel Robert Koch, I’d propose that one should use some of the archival material to seed misfolding of recombinant amyloid beta, and us a seed of that to nucleate misfolding of more recombinant amyloid beta…and then try to induce the disease in humanized mice before announcing that I’d identified the causative agent (dare I call that a”pathogen”??)

  13. Project Osprey says:

    Random thought: Some forms of Alzheimer’s disease are thought to be genetic. Is there any possibility that they’re caused less by genetics and more by living with someone who’s constantly shedding tiny amounts of misfolded protein?

    1. loupgarous says:

      John Collinge’s team reported over 80% of new variant CJD patients lacked the HLA-DQ7 version of the human leucocyte antigen protein. About 35% of nomal, healthy people have that version of the HLA protein, but only 12% of 50 nvCJD patients studies by Collinge and his team.

      It could be we’re looking at both a genetically transmitted proneness to contracting AD and environmental exposure to the causative agent.

      A blood relative of an AD patient or a spouse among the 65% of healthy folks who lack HLA-DQ7 who inhales misfolded protein shed by someone ill with a prion disease would be more likely to contract the disease than a stranger or a household member with HLA-DQ7 and whatever protective effect it affords people who have it.

      1. Ben says:

        Is there any possibility that we are talking about a single symptom of several distinct diseases?

        (Sorry, non-specialist here)

        1. lola says:

          Hello Ben
          Absolutely: most cases of neurogenerative diseases that result in death are obviously not autopsied to the level require to determine the neurochemistry of either neuronal architecture or composition. So yes, we don’t know – your comment may be prescient!

  14. T says:

    How is transmission following intramuscular injection “firmly supported” by results from intracerebral injection? Why didn’t they use the same application route in the mice?

    1. Toni says:

      Good question. Either the transmission doesn’t work via blood or a mouse life is too short to show this.

  15. CB says:

    The next step is the finding that self-assembled ordered structures of small molecules in food, drugs, perfumes and metabolites seed amyloidogenic proteins.

    In this regard read the recent article in J Mol Biol (2018) 430, 3847–3862: “Quinolinic Acid Amyloid-like Fibrillar Assemblies Seed α-Synuclein Aggregation”

    and from this paper: “Quinolinic acid (QA), a downstream neurometabolite in the kynurenine pathway, the biosynthetic pathway of tryptophan, is associated with neurodegenerative diseases pathology.
    We recently established that self-assembled ordered structures are formed by various metabolites and hypothesized that these “metabolite amyloids” may seed amyloidogenic proteins. Here we demonstrate the formation of QA amyloid-like fibrillar assemblies and seeding of α-synuclein aggregation by these nanostructures both in vitro and in cell culture”

  16. Scott says:

    I have this nasty suspicion that beta-amyloid plaques are effectively *equivalent to scar tissue*. The plaques happen long after the damage has been done, and are a response to that damage, not the cause of the damage.

    But I’ve also seen some psychological ’causes’ of Alzheimers/dementia. After my grandmother passed, grandpa went from not-quite-recognizing people to completely lost, going from 4 to 40 to 80 in sentences. And it was just about instant.

    1. luysii says:

      Scott — Unfortunately, clinically this is quite common. By her very existence, your grandmother was feeding your grandfather cues from the far past (which Alzheimer patients retain) keeping him oriented. Similarly, when such a patient leaves home and familiar surroundings they fall apart. I’ve seen this many times and would call a social worker in before the intact partner passed.

      1. Lola says:

        @luysii
        Thanks for that comment. I have seen this clinicially too, and felt we can almost predict a patient’s pathway/outcome once a partner or loved one is removed (read ‘died before them’). I’m reluctant to explain this to patients, not having any evidence base for it but a strong feeling, but have often subtly explained the loss of their ‘circumstances’ may result in a faster decline. I believe (but don’t know for sure) that it’s the effect on the loss of ‘stimulation’ if you like of old memories that invites the more rapid downfall of these patients. I’m not averse to the idea it’s also an effect of a subtle depression too – but that’s another issue. I’ve often wondered that a study here would be useful – not that we have much to mitigate the effect clinically – hence my reluctance to be too definitive about it.

  17. asfgd says:

    Honestly the more neurodegenerative disease news I read the more suicidal I get. Having lived with relatives suffering from dementia I want to keep my own future family from suffering like my family did. I think at this moment it’s fairly clear that preventative treatments for neurodegenerative disorders should start in childhood, so it’s too late for me.

    1. Derek Lowe says:

      Ah, but keep this in mind: people have looked for years for genetic components for things like Alzheimer’s, and outside of the really overt mutations (the Swedish, Dutch, etc.) it’s been very hard to find any. And what shows up as dementia can be Alzheimer’s, or cerebrovascular disease, or something else entirely – the only way to be sure of an Alzheimer’s diagnosis has been autopsy (although imaging techniques are getting better).

      So don’t despair. Keep yourself healthy (exercise, reasonable diet) and watch your blood pressure, etc. The only genetic links to neurodegeneration that we know about would have hit already, so for you, the future is unwritten. There are no guarantees, but there’s no prewritten doom, either.

  18. Tim C. says:

    https://europepmc.org/abstract/med/20170305

    Interestingly enough, neurosurgeons appear to be at elevated risk of Parkinsons and Alzheimers, indicating that there might be a chance that exposure is causing some level of transmission

    1. SnupSnus says:

      I don’t think this is the right conclusion. Neurosurgeons in the sample had reduced mortality from other causes, Alzheimer mortality is likely due to the fact that they live longer and don’t die of the disease that kill you before you get Alzheimers. Also don’t fly if you are a neurosurgeon… Could do worse than having dying from aircraft accidents as your professional risk

  19. Thoryke says:

    Speaking of “giving people illnesses” via contaminated equipment: https://www.mcall.com/news/breaking/mc-nws-nj-healthplus-safety-lacking-20181229-story.html

  20. FoodScientist says:

    Oxidative stress seems like a plausible area to look into. Someone needs to do a really good study with clearly defined groups of people from different phenotypes/genotypes and smoking status. This would be a really plausible mechanism for the protective effect seen in apoe4 carriers and possible the opposite for non carriers.

  21. still, the question ayrse why some people can have plaques and not develop clinical AD, differing susceptibility is a possibility, these mouse models are chosen to be prone to plaques and amyloid angiopathy.

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