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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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October 6, 2011

Is Alzheimer's An Infectious Disease? The Spread of Protein Misfolding

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Posted by Derek

That's what this paper in Molecular Psychiatry is suggesting. The authors injected material from human Alzheimer's patients into the brains of normal mice, and saw what appears to be the induction of amyloid pathlology. This didn't happen in control animals, got worse with time, and wasn't just noted at the point of injection. Their hypothesis is that Alzheimer's might be a prion-type disease of protein misfolding, and possibly capable of being spread by infectious particles. I recall ideas like this being advanced in the past, but this is the first time I've seen evidence like this (hasn't this sort of experiment been run before?) It's simultaneously fascinating and alarming, and I would very much like to see it repeated and confirmed.

This comes as broadly similar ideas are being advanced in Parkinson's disease, where recent work has shown misfolded alpha-synuclein protein (long known as a key factor) spreading slowly through infected neurons. No one has ever seen evidence of transmissible Parkinson's between humans, but it does seem to move between neurons like an internal epidemic.

And that comes as broadly similar ideas are being advanced in ALS. A recent paper in PNAS suggests that a mutant form of superoxide dismutase 1 (which had already been found to be associated with the disease) can be spread by the injection of precursor cells that express it. That makes you think that the SOD1 mutant (G93A, which is not the most common mutation in humans) may also have prion-like properties, and can induce other proteins to misfold along with it. What's especially interesting (and again, rather alarming) is that it apparently can recruit normal SOD1 into this state. (In this study, though, the effects were confined to the region around the introduction of the cells, so the spread was not that fast). It's important to note again that, as in the case of Parkinson's, no one has ever seen evidence that ALS is transmissible from person to person - in fact, I don't think that anyone has ever seen ALS in anyone without the mutation in their genome. But this does shed some light on what happens internally.

So taken together, the spreading-protein-misfolding mechanism seems to have a lot of momentum behind it. The big question is whether it can result in human-to-human transmission. Even in the cases where we've confirmed prion-based disease, transmission seems (fortunately) rather difficult, although this is a very active field of research, and definitely something to keep an eye on. The possible Alzheimer's connection is especially interesting, since that one is simultaneously more common and does not have a strong genetic component. It occurs (as far as we can tell) mostly sporadically. The amyloid hypothesis for its cause has been taking some hits in recent years, but the other side of the story is still very much alive. . .

Comments (41) + TrackBacks (0) | Category: The Central Nervous System


COMMENTS

1. Curious Wavefunction on October 6, 2011 7:58 AM writes...

I have to read the paper but I thought this was already known with CJD and BSE. I think it's nicely documented in Richard Rhodes's "Deadly Feasts".

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2. luysii on October 6, 2011 8:09 AM writes...

Well, if ALS is transmissible, former muscular dystrophy clinic directors (such as myself) should have an increased incidence of it. Neurologists as a group should also have more Parkinsonism and Alzheimer's disease if those diseases are transmissible. Spouses of these patients should have an even greater incidence of these diseases, but as far as I know, they don't.

There is something to the idea of local spread -- embryonic dopamine neurons implanted into the striatum (a part of the brain) of patients with Parkinsonism 11 - 14 years earlier, develop Lewy bodies (aggregates of the alpha-synuclein protein along with other proteins) and degenerate [ Nature Med. vol. 14 pp. 501 - 503, 504 - 506 '08 ]

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3. Derek Lowe on October 6, 2011 8:37 AM writes...

Wavefunction, that's right - those are the prion diseases that we know can be transmitted, and if you incorporate tranmissibility in the definition of "prion" (as many do) then these other diseases don't (yet) fit.

And that gets to luysii's point. I agree that there's no evidence at all that ALS is transmissible (and plenty of genetic evidence that it's not). Parkinson's has a less clear genetic character (to put it mildly), but there's still no evidence for its transmission. And Alzheimer's is in a similar situation - there are a few genetic markers (like APOE4), without much to pin them on mechanistically (and I'm leaving out the Dutch and Swedish mutations, since they're special cases). But the incidence rate is higher than the other diseases, which suggests that an infectious route might have a (slightly) better chance of being true.

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4. VIrgil on October 6, 2011 8:43 AM writes...

Where did you get the paper?

DOI link is borked.
Neuron (the journal) website does not list it.
PubMed Search for authors does not find it in NCBI database
Search for title in PubMed also a dead end.

Sure, Googling the title brings up lots of news hits, referring to the story, but the paper itself does not appear to be available yet.

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5. Anonymous on October 6, 2011 8:49 AM writes...

"in fact, I don't think that anyone has ever seen ALS in anyone without the mutation in their genome."

Mutations in SOD1 only account for a small subset of familial ALS. The majority are sporadic ALS, with no mutations in SOD1, and surprisingly wildtype (not mutant!) SOD1 has been shown to be implicated in the sporadic form through a misfolded confirmation. Protein misfolding yet again...

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6. darwin on October 6, 2011 9:08 AM writes...

advocate of this hypothesis-senescence of protein folding machinery, transport and checkpoints in a highly orchestrated process such as folding is at root of all these dementias...proving once again Mother Nature doesnt give a damn once we have fulfilled reproductive capacity.

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7. luysii on October 6, 2011 9:11 AM writes...

#5 "surprisingly wildtype (not mutant!) SOD1 has been shown to be implicated in the sporadic form (of ALS) through a misfolded confirmation."

It is more than surprising. How about a reference?

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8. luysii on October 6, 2011 9:12 AM writes...

#5 "surprisingly wildtype (not mutant!) SOD1 has been shown to be implicated in the sporadic form (of ALS) through a misfolded confirmation."

It is more than surprising. How about a reference?

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9. HelicalZz on October 6, 2011 9:13 AM writes...

Their hypothesis is that Alzheimer's might be a prion-type disease of protein misfolding, and possibly capable of being spread by infectious particles.

I don't follow this literature, but I do have the impression that it has been pointing for awhile toward a 'seeding' type of event, much like in crystal formation. This would most probably be due to oxidative stress / radical alteration, which could drive a folding change, which could serve as a seed for the aggregation of normally folded proteins. That isn't inconsistent with it appearing 'infectious' under the right conditions.

Won't surprise me if Alzheimer's shows itself to be more preventable than curable. If the above shows to be a correct speculation, it would be very difficult to drug (and even harder to clinically evaluate).

Zz

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10. luysii on October 6, 2011 9:16 AM writes...

#5 "surprisingly wildtype (not mutant!) SOD1 has been shown to be implicated in the sporadic form (of ALS) through a misfolded confirmation."

It is more than surprising. How about a reference?

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11. luysii on October 6, 2011 9:16 AM writes...

#5 "surprisingly wildtype (not mutant!) SOD1 has been shown to be implicated in the sporadic form (of ALS) through a misfolded confirmation."

It is more than surprising. How about a reference?

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12. Anonymous on October 6, 2011 9:18 AM writes...

#2 "Well, if ALS is transmissible, former muscular dystrophy clinic directors (such as myself) should have an increased incidence of it. Neurologists as a group should also have more Parkinsonism and Alzheimer's disease if those diseases are transmissible."

Are you suggeesting you eat your patients?

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13. anchor on October 6, 2011 9:19 AM writes...

A very compelling argument that need to be substantiated by further studies. I am worried if this is going to cause confusion and chaos. If prions are indeed involved, then we have more patient population who are carriers for AD. Another thing that had me worried is the blood supply. I mean the storage with blood bank and it will probably eliminate some from giving blood for good. Is there is any diagnostic reagents (antibodies) for prions? Lot of questions indeed.

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14. Mrten on October 6, 2011 9:22 AM writes...

Well, perhaps not human-human infectious directly, but indirectly via food a la BSE?

(Speaking as a *complete* layman so don't be too hard on me)

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15. anon the II on October 6, 2011 9:24 AM writes...

This is all like ice-9 in slow motion.

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16. Anonymous on October 6, 2011 9:27 AM writes...

# 7 (and 8, 10 and 11): Surely. Here's the reference:

Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS.
in Nature Neuro, Nov., 2010

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17. bmartinmd on October 6, 2011 9:29 AM writes...

You ask parenthetically, "Hasn't this sort of experiment been run before?"

The answer appears to be at least once, but with negative results.

I know of a few, namely 2, articles that suggest a potential overlap between the pathology of AD and prion diseases--including one by Morales et al from 2010 (essentially the same authors of the current Mol Psych article).

As far as "seeding" studies are concerned, Kane et al in 2000 (from Parke-Davis) reported a similar experiment in APP-transgenic mice, but they found no induction of deposits in nontransgenic mice, as far as I can tell.

What studies do Morales et al of the current Mol Psych article cite in their background or discussion (I do not have full access to the article)?

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18. Guppy on October 6, 2011 9:59 AM writes...

There's been some hints that leaky blood-brain barriers are associated with Alzheimers. If prion-mediated, I suppose it's plausible we could be looking at the entry route.

Also, a rare reaction to a common agent can also look sporadic.

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19. Derek Lowe on October 6, 2011 10:14 AM writes...

Virgil, I got it from a link at Science Daily:

http://www.sciencedaily.com/releases/2011/10/111004113757.htm

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20. luysii on October 6, 2011 10:40 AM writes...

#12 Transmissible means just that, with no implication as to mechanism -- which took years to discover for Kuru. Remember TB was thought to be hereditary before the organism was discovered, and there was great worry that scrapie of sheep was in some way causative of multiple sclerosis for a time.

Hypotheses non fingo

Permalink to Comment

21. luysii on October 6, 2011 10:42 AM writes...

#12 Transmissible means just that, with no implication as to mechanism -- which took years to discover for Kuru. Remember TB was thought to be hereditary before the organism was discovered, and there was great worry that scrapie of sheep was in some way causative of multiple sclerosis for a time.

Hypotheses non fingo

Permalink to Comment

22. Conformist on October 6, 2011 10:54 AM writes...

The idea that researchers or physicians could contract amyloid diseases (other than nvCJD or other established prion diseases) from samples or patients is both frightening and plausible.
George Glenner was one of the first scientists to develop an understanding of the role of beta-amyloid peptide in the molecular pathogenesis of Alzheimer's Disease. Unfortunately, his death was due to systemic amyloidosis.

Permalink to Comment

23. cynical1 on October 6, 2011 12:04 PM writes...

I think this study finally explains all the zombie movies I've seen!

Pretty cool but if it's true, we're really screwed on the drug discovery end.

Just to be safe, I'm keeping my mother-in-law away permanently. I don't want to catch anything.

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24. passionlessDrone on October 6, 2011 12:29 PM writes...

#23: +1


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25. Curious Wavefunction on October 6, 2011 12:54 PM writes...

luysii@3: True, but shouldn't it depend on the mode of transmission? Maybe the other diseases are transmissible only through blood-blood contact in which case you wouldn't expect spouses or neurologists to catch them too easily.

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26. Norman Yarvin on October 6, 2011 3:24 PM writes...

Why are they jumping straight to prions? From the sounds of the sciencedaily.com article, any infectious disease would fit. (For that matter, isn't there still room for doubt about whether prions actually are causal? Or has someone done a really definitive experiment, like generating pure prion protein via genetic engineering and showing that it can cause disease?)

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27. Trep on October 6, 2011 3:53 PM writes...

I agree that this is kind of jumping to conclusions. You'd think there would be some epidemiological data to support this. It's not like Alzheimer's is a rare disease like CJD, there are tens of millions of people who have AD. A tumor is also infectious if you inject it into someone else's brain. Now they have a tumor.

The concept of cell-to-cell transmission however, is quite interesting, particularly with the spatial progression of diseases such as Parkinson's.

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28. pete on October 6, 2011 6:41 PM writes...

@27 Trep
- ditto that

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29. johnnyboy on October 6, 2011 9:04 PM writes...

I don't think the authors are making the conclusion that AD is infectious and transmissible, at least not from the abstract, in which there is no mention of transmission. They just posit this finding as a possible mechanism of amyloid buildup in AD.

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30. Incha on October 6, 2011 9:09 PM writes...

This may be a very stupid comment (and feel free to say so), but if you inject a rodent with cancer cells they get cancer, and noone seems to claim that is infectious.

Does this perhaps show us that amyloid is like a crystal, its a lot easier to form if it has a seed?

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31. John on October 6, 2011 9:27 PM writes...

I am skeptical of this finding. Previous work using non-human primates failed to demonstrate transmissiblity using 17 cases of AD. Two cases showed transmission however it was similar in pathology to CJD which could be explained by contamination.

Evidence for and against the transmissibility of Alzheimer disease.

Goudsmit J, Morrow CH, Asher DM, Yanagihara RT, Masters CL, Gibbs CJ Jr, Gajdusek DC.

Neurology. 1980 Sep;30(9):945-50.

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32. John on October 6, 2011 9:27 PM writes...

I am skeptical of this finding. Previous work using non-human primates failed to demonstrate transmissiblity using 17 cases of AD. Two cases showed transmission however it was similar in pathology to CJD which could be explained by contamination.

Evidence for and against the transmissibility of Alzheimer disease.

Goudsmit J, Morrow CH, Asher DM, Yanagihara RT, Masters CL, Gibbs CJ Jr, Gajdusek DC.

Neurology. 1980 Sep;30(9):945-50.

Permalink to Comment

33. Anonymous on October 6, 2011 10:00 PM writes...

To think that an injection of brain matter into the brain of healthy mice equates a risk of transmission is just silly. You'd be hard pressed to find some sort of transmission mechanism that would lead to a cascade of protein misfolding in the brain from external contact with some diseased tissue or the like.

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34. Jonathan on October 7, 2011 10:32 AM writes...

As I understand it, the evidence is pointing more and more to AD being an inflammatory disease, so a pathogenic initial insult seems fairly reasonable. There also seems to be evidence pointing to traumatic brain injuries as possible initiating factors, which often result from human-human contact, if you catch my drift.

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35. CB on October 7, 2011 12:06 PM writes...

Ten years ago I was extremely skeptical of the whole prion hypothesis.
However, he bulk of the research seems to be pointing to prion intermediates, on the path to formation of the amyloid fibers, as the toxic form of the protein.

A number of researcher consider these diseases to be kinetically driven, seeded nucleation processes, enhanced by specific mutations or other physiological insults that drive formation of this toxic intermediate.

The large fibrous tangles that arise in the brain are considered to be non-toxic to cells in vivo. However the oligomeric intermediates (which can be prepared by breaking up the large tangles) have been demonstrated to be deadly.

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36. DrSAR on October 8, 2011 11:01 PM writes...

@Incha (30): there are tumours that are transmissible: CTVT, and Devil facial tumour disease that seems on course to eradicate the poor Tasmanian Devils. If you include tumour-causing infections, transmission is an actually important part of some tumour's etiology (which is also why we now have a HPV *vaccination* that we hope will help with cervical cancer)

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37. Anonymous on October 10, 2011 9:10 PM writes...

None of this matters anyways...we are only 10-30 years away from complete head transplants! Lop the old one off and connect the other.LOL!

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38. Northwest AJ on October 13, 2011 5:17 AM writes...

#31: I've heard speculations that some percentage of Alzheimer's cases are actually misdiagnosed CJD. (Which is frightening if true, in that it points to a far higher prevalence than estimated for CJD...) This may be connected to the inconsistency in research results.

The idea that the protein misfolding in Alzheimer's is always transmissible is far scarier, though. It takes crazystupid amounts of sterilization to get rid of prions on surgical instruments and such.

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39. CSANTOS on October 26, 2011 6:30 PM writes...

So basically what this article/abstract/paper/whatever is implying is that if Alzheimer's is anything like "mad-cow disease" then If you somehow ingest the muscle of a carrier//victim/patient with Alzheimer's you will most likely become "infected" with the disease.

Interesting.

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40. David Hill on January 3, 2012 1:15 PM writes...

The UK DoH has carried out extensive research into vCJD and created risk models predicated upon the estimated number of carriers, (around 10,000 individuals (est)) with a view to determining actions such as improvements in decontamination practice for surgical instruments and notably the risk models were weighted towards risk associated with medical procedures that involve neural tissues. If either the number of carriers IS being misdiagnosed OR if AD may be caused by contaminated instruments - would a re-evaluation of these risk models be likely to present an imperative for further improvements in decontamination processes. Procedures involving neural tissues are small in number compared to those involving blood per se. (ie dental).

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41. Phil on February 10, 2012 10:27 AM writes...

I'm intrigued by the theory that prions may be responsible for the transmission of AD. Regarding the seemingly contradictory evidence that if it is transmittable, we should see a higher incidence of AD among those who work with AD -- keep in mind that some prion-caused diseases seem to have a long "incubation" period. I've read that one Kuru victim took 50 years from ingesting a deadly feast until he/she died. I know this may be wild speculation, but AD is reported to occur at a decreased incidence among vegetarians, and the incidence in India (where Hindu dietary customs predominate)is reported to be much lower than in the West. Could this be faint evidence of a possible meat-related transmission link?

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