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Alzheimer's Disease

Beta-Amyloid: An Antibiotic?

Now here’s something that I don’t think anyone expected. A recent paper in PLoS One makes the case that beta-amyloid, the protein that has been fingered for decades as a major player in Alzheimer’s disease, is actually part of the body’s antimicrobial defenses.
Well, it’s good to hear that it’s doing something. Many people had hypothesized that it was a useless (indeed, harmful) byproduct, a waste stream from aberrant processing of the amyloid precursor protein (APP). Still, there have been reports over the years that beta-amyloid was substrate for active transport pumps, might be a ligand for various receptors, etc., but not everyone was willing to take these results seriously.
But it turns out that some of A-beta’s properties are similar to those of innate host defense peptides. When this latest team checked the amyloid protein’s activity, it turns out to be pretty active. The prototype peptide in this area, LL-37, appears to have a broader spectrum of activity, but A-beta beats it against several organisms, most notably the yeast C. albicans. And as it turns out, brain homogenates from Alzheimer’s patients are much more active against yeast in vitro than samples from age-matched controls without the disease. But that only holds true for parts of the brain (like the temporal lobe) that are known to be high in amyloid. Samples from the cerebellum (which doesn’t usually show Alzheimer’s pathology) had no activity. (One has to wonder if this is the first time – or at least the first time in a very long while – that anyone’s evaluated human brain homogenates for their microbicidal activity).
This could lead to a complete rethink of Alzheimer’s pathology. It’s been known for a long time that there’s a big inflammation component to the disease – perhaps the problem (or at least the trigger) is an underlying infection that sets off the innate immune system in the brain. Larger than normal amounts of beta-amyloid are produced in response, but it starts to precipitate out.
The more familiar adaptive immune system has limited access to the CNS, although that’s not stopping people from trying to use it. But that approach (and many others) presume that beta-amyloid is a cause of the disease. Perhaps it isn’t. Maybe it’s the body’s attempt at a solution – and if that’s true, we need to look elsewhere for the cause, and soon. This is one of the most thought-provoking looks at Alzheimer’s that I’ve seen in a long time. Here’s hoping it leads to something new.
Update: here are some more comments on this paper, and here are some speculations about amyloid as a protective agent.

25 comments on “Beta-Amyloid: An Antibiotic?”

  1. Curious says:

    Interesting that this appeared in PLoS, not one of the “mainstream” major journals. Might those journals have suppressed it?

  2. sgcox says:

    Well, I don’t think you can slip past referees something like Fig.3B in Nature or Science. Plos One is a about right for such paper.

  3. Daniel says:

    Figure 3B confuses me…

  4. p says:

    Sounds similar to type 1 diabetes, doesn’t it?

  5. Derek Lowe says:

    I have to say, Figure 3B (plotting growth of C. albicans vs. amount of amyloid in the brain homogenates) is one of the least convincing correlations I’ve seen in a while. I don’t know how good the ELISA antibodies are for this assay, but if they’re lousy enough to be reason for the scatter, they’re lousy enough not to do the assay.

  6. qetzal says:

    I saw this discussed a few days ago on the blog Neurophilosophy. Interestingly, there is some published data suggesting that Alzheimer’s-like pathologies can be caused in mice by Chlamydia infection.

  7. Sili says:

    But why would the infection (yeast or otherwise) be specific to the temporal lobe and avoid the cerebellum? What makes them differentially susceptible?

  8. Hap says:

    #2: You mean, like this? Or this one?
    I think you’re being optimistic.

  9. cynical1 says:

    Sili – many infectious agents are specific for various tissue types, for instance latent and lytic infection of herpes viruses restricted to neuronal, T-cell, B-cells, and epithelial cells. Also, the infection may not be restricted to one tissue type but the inflamatory response and protein buildup could be restricted. Also, as has been shown with HTLV-1 infection in tropical spastic paraparesis, measles virus in subacute sclerosis panecephalitis, and EBV in MS, the inflammation and tissue damage is immunologically mediated in the absence of the infectious agent through mechanisms that are unique in each case to the infectious agent.

  10. Wavefunction says:

    Hi Derek, a while ago I had a long speculative post arguing that amyloid evolved as defense against infection. However my hypothesis is that it binds to metals and produces free radicals which kill bugs. I would be interested in your comments on the post.

  11. RB Woodweird says:

    It’s pretty clear that beta-amyloid is the brain trying to protect itself from cell phone radiation.

  12. Andrew Ryan says:

    Another paper suggests that TLR2, a receptor that triggers inflammation in response to bacterial lipoproteins, also recognizes amyloid fibers in bacterial biofilms. One possibility is that TLR2 evolved to recognize bacterial biofilms and one consequence is that recognition of endogenous amyloid fibers in Alzheimer’s leads to brain inflammation.

  13. gibby says:

    So there’s also been a significant buzz lately about alzheimers as type 3 diabetes. That it can be triggered, or made worse by insulin resistance in the brain. I do know that amyloid peptides do in fact bind the insulin receptors. One has to wonder if this is part of a protective function, and if it’s part of contributing to the disease progression.

  14. gibby says:

    Is there a link between chronic cocaine use and alzheimers? One might just think that the white stuff messes up the brain, but in fact it can bring about some serious breakdown of nasal membranes and infections in the sinuses and even into the brain (I believe I’ve read this). If thats so it may help to support this infection model

  15. ron richardson says:

    I don’t see how any of this is surprising. A-beta forms highly toxic oligomeric species. These things kill the crap out of neurons. Guess what, they also kill most other cells, human, yeast, bacterial, whatever. It’s toxic, it kills stuff…this just shows that it’s toxicity is through fairly broad mechanisms, like poking holes in membranes…

  16. anchor says:

    An interesting paper (other than incoherent plot 3B). The infection of brain though rare can occur and more so for immune compromised. Toxoplasma gondii is one such pathogen than can infect people suffering with AIDS. I am curious if beta-amyloids can stand up to T. gondii. Comments welcome.

  17. Sili says:

    One might just think that the white stuff messes up the brain, but in fact it can bring about some serious breakdown of nasal membranes and infections in the sinuses and even into the brain (I believe I’ve read this).

    I thought that decay was due to cocaine being distributed as the hydrochloric salt. People were essentially snorting HCl.
    Thank you, cynical1. It should be fairly obvious that I have little knowledge of the human body.

  18. Tuck says:

    Not skilled in the art, so this may be a dumb idea, but: could plot 3B simply suggest an almost flat “dose/response” as opposed to sloppiness in methodology that commenters here seem to be implying? If I am reading the discussion section correctly, the authors are suggesting synergy with another AMP(s), which would also be swimming around in that homogenate. Further investigation of that concept might be fruitful.

  19. Tuck says:

    Nevermind. I just got to supporting information part 1, where they show data saying it IS dose dependent. Now I’m as confused as everyone else about 3B.

  20. AJL says:

    I’m surprised no one has mentioned prions yet.

  21. Tom M. says:

    Some think there is a causative link between Lyme Disease and Alzheimers, c.f.,

  22. Gunni says:

    I am really into neurovascular congruence, and firmly believe that there are vascular flaws that increase oxidative stress. These in turn increase the liklihood of plaque formation. I think that the vascular problems underly the majority of neuronal degenerative disorders.

  23. Eli Kammerman says:

    My 2006 publication (excerpt below) explicitly described Aβ as an antimicrobial peptide based on its multiple similarities to melittin.
    In addition, the described antimicrobial action was explicitly cited as a basis for Aβ to be considered a component of the innate immune system, likely as a rapid response to infections by enveloped viruses such as HSV.
    Excerpt from Kammerman et al., 2006:
    “Numerous groups have reported that Aβ42 can disrupt lipid membranes by creating pore-like holes (ion channels) within the membranes. This property of Aβ42 appears to be related to an antimicrobial function; nature is replete with examples of peptide antimicrobials that effect their function through membrane disruption. In fact, some of these peptides show strong activity against HSV-1. For example, melittin, which has an α-helical amphipathic structure similar to Aβ42, has anti-HSV activity. We assert that β amyloid, by virtue of its similar molecular shape and size, is a peptide antimicrobial component of the innate immune system which can neutralize enveloped viruses such as HSV-1. We contend accordingly that ion-channel pore formation in the HSV-1 envelope generated by Aβ42 is virucidal.”
    Kammerman EM, Neumann DM, Ball MJ, Lukiw W, Hill JM. Senile plaques in Alzheimer’s diseased brains: possible association of beta-amyloid with herpes simplex virus type 1 (HSV-1) L-particles. Med Hypotheses. 2006;66(2):294-9.

  24. Keith Hanson says:

    Think this out. Is there maybe a connection to the process of Sarcoidosis???. The surrounding of an intruder into the body with a vitamin D and calcite cover// Not unlike what happens in an oyster when a grain of sand gets inside.

  25. ron davison says:

    T cell count and other markers should show a correlation. spinal fluid even better but probably not very useful because of the intrusiveness just for Alzheimer studies. But if a co-op between doctors doing spinal taps anyway for other reasons where to allow for tracking these paitents over time, and allowing for other tests and possibly brain scans for baselining brain volume early enough data could be colected for statisticaly valid #S for correlation. Could byproducts of infection in the body that can get past the blood brain barrier trigger the pre-amaloid response?
    Could the over production of amaloid be an over reaction or the system not recognizing the threat is removed and the pre-amaloid is continued to be made in alzheimers with a genetic predisposition?
    Are there other mechanisms in the brain to protect itself that are missing in genetically at risk individuals so that the Pre-amaloid is the only protective mechanism and thus gets put in “overdrive”?
    Are an exessively acidic or oxidative food/water intake make this worse? Has ther been any studies done to see if there is correlation to acidic water/diet and Alkaline water diet based on region or cultural eating habits? If so then this should add to risk of genetically at risk individuals with Alzheimers?

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