Fungi in the Alzheimer’s brain and changing views on amyloid beta

November 18th, 2015 by Amy Proal
candida-albicans
Fungal species in different brain regions of patients with Alzheimers. (Soscia et al.)

Fungal species in different brain regions of patients with Alzheimers. (Pisa et al.)

Just a few days after writing my last post on microbes in the brain, I read a study that shows even more evidence of chronic infectious agents in brain tissue. In a paper published this month, Pisa and team at the Universidad Autónoma de Madrid studied the brains of patients with Alzheimer’s disease (AD). They found that all eleven AD brains studied were infected with a range of fungal organisms.

I am not surprised by the discovery. For one thing, inflammation of the central nervous system and immune activation play a major role in driving the Alzheimer’s disease process. Indeed, a number of cytokines, or immune system signaling molecules, are elevated in the brain of AD patients. This strongly suggests an activated immune response against pathogens. These cytokines include interleukins, tumor necrosis factor-α, and interferon-γ.

The hallmark of the disease is amyloid beta, a compound that accumulates in the AD brain. In 2009, Soscia and team at Massachusetts General Hospital reported that amyloid beta is not a harmful byproduct but an antimicrobial peptide. Antimicrobial peptides are natural, broad spectrum antibiotics created by the body that destroy bacteria, enveloped viruses, fungi and even transformed or cancerous cells. Soscia’s work undermines long-standing explanations for the disease.

To give more context, researchers have long noted the presence of amyloid beta in the brains of patients with Alzheimer’s. Such amyloid beta deposits or “plaques” were assumed to be harmful. As a consequence, mainstream medicine adopted the “amyloid hypothesis.” According to the hypothesis, the accumulation of amyloid beta in the AD brain is the primary driver of the disease process, and formation of the neurofibrillary tangles that characterize Alzheimer’s results from an imbalance between amyloid beta production and amyloid beta clearance.

Soscia and team’s discovery strongly suggests that the “amyloid hypothesis” is completely misguided. If amyloid beta is an antimicrobial peptide, then it serves a protective role in patients with Alzheimer’s. In other words, amyloid beta almost certainly accumulates in the brains of AD patients as part of an effort by the body to combat pathogens in the area. In fact, Soscia and team found that, in the laboratory, amyloid beta inhibited the growth of eight important pathogens screened by the study (see chart to the right). These included the bacterium S. pneumoniae, which is the leading cause of bacterial meningitis.

journal.pone.0009505.t001

The antimicrobial activity of synthetic forms of amyloid beta and LL-37 were determined as minimal inhibitory concentrations against 12 microorganisms

The pathogen that Soscia and team identified as being most sensitive to amyloid beta is the fungus Candida albicans. This squares perfectly with Pisa and team’s recent finding of fungi in the Alzheimer’s brain. Indeed, Soscia and team found that the antimicrobial activity of amyloid beta was so strong that in some cases, its activity exceeded that of LL-37 – one of the body’s most potent and broad-spectrum antimicrobial peptides.

Soscia and team additionally tested whether the antimicrobial activity of amyloid beta observed in a laboratory setting could be identified in the temporal lobe and cerebellum of human brains. They found that Alzheimer’s temporal lobe samples contained an average of 24% greater activity against C. albicans than samples from non-Alzheimer’s subjects.

In the end, the team concluded that:

..our finding that amyloid beta is an antimicrobial peptide is the first evidence that the species responsible for amyloidosis (accumulation of amyloid beta) may have a normal function. This stands in stark contrast to current models, which assume amyloid beta deposition to be an accidental process resulting from the abnormal behavior of an incidental product of catabolism (breakdown). Our data suggest increased amyloid beta generation, and resulting Alzheimer’s pathology, may be a mediated response of the innate immune system to a perceived infection.

Exactly. An antimicrobial peptide would only logically accumulate in an area of the body if the region is infected with a pathogen, or multiple pathogens. Indeed, several clinical trials aimed at lowering amyloid beta levels in Alzheimer’s patients have failed. This is almost certainly because such trials incorrectly removed a potent antibiotic compound, and not problematic “plaque”, from the brains of their subjects.

That brings me back to the Pisa and team study, which is described at the end of this article in further depth. In their paper, Pisa and team point out that the gradual progression of Alzheimer’s disease is consistent with the chronic nature of fungal infection. They comment that,

It is quite possible that the existence of one fungal infection may facilitate the colonisation by other fungal species that can affect other areas of the CNS, giving rise to mixed fungal infections. The diversity of fungal species that can affect the CNS, as well as the combinations of these species, may account for the observed differences in the evolution and severity of clinical symptoms found in AD patients.

Fungal bodes detected in CNS sections of an Alzheimers patient Pisa et al.)

Fungal bodes detected in CNS sections of an Alzheimers patient (Pisa et al.)

This observation supports the hypothesis of successive infection that I have put forth in many of my research papers. The hypothesis contends that even in patients with the same diagnosis, symptoms may diverge as a result of the unique manner in which pathogens accumulate in any given person. It is important to note, however, that pathogens other than fungi have been detected in the brains of patients with Alzheimer’s. These include the bacterium Chlamydophila pneumoniae and herpes simplex type 1 (HSV-1). This means that other microbes almost certainly contribute to the Alzheimer’s disease state in conjunction with any fungal species. In fact, if I had to guess, I think it’s very possible that in Alzheimer’s disease, bacterial and viral pathogens slow the immune response in a manner that makes it easier for fungi to colonize the brain over time. But much more research on the topic is clearly needed.

Lastly, the Pisa and team study begs the question: could antifungal medications help patients with Alzheimer’s? The team points out that a number of highly effective antifungal medicines exist today. They go on to reference two case reports in the Journal of Alzheimer’s Disease in which patients with Alzheimer’s symptoms appear to recover after treatment with antifungal drugs. The results are extremely preliminary, but thought-provoking nonetheless.

More on the Pisa and team study

In order to derive preliminary data, Pisa and team examined an AD brain, and the brain of a control subject without any known disease. Both brains were removed from patients after autopsy. The brains were stained with a dye that causes proteins associated with fungus C. glabrata to change color. In the AD brain, the team detected the presence of fungal cells in four different brain regions. No fungal cells or fungal material were detected in the brain of the control subjects. In the AD brain however, fungal cells were clearly visible both inside and outside brain cells called neurons. These intracellular fungal forms are known as endomycosomes. Fungal bodies in the AD brains varied in size; some were quite small, while others were significantly larger.

Pisa and team then searched for the presence of fungi in ten more AD brains, and ten more control subject brains. This time however, they stained for proteins associated with several additional fungal species – C. famata, C. albicans. P. betae, and S. racemosum. While not all AD brains analyzed contained every fungal species, each contained at least some combination of the different microbes. This second analysis also detected long fibrular structures clearly resembling fungal hyphae in the AD brains. Analyses of tissue sections from the ten control subjects again failed to reveal any fungal material.

The majority of AD patients exhibit lesions or tears in the blood vessels of the central nervous system. Indeed, a subsequent analysis detected fungal cells of different sizes and hyphae inside capillaries and other blood vessels of four AD brains. Some staining consistent with the presence of various species of fungi was also evident in the blood vessel walls of these samples. The cerebral blood vessels of control subjects again did not show evidence of fungal infection.

In order to determine if additional fungal species might be present in brain tissue, Pisa and team used a molecular technology called PCR to amplify and sequence fungal DNA from the frozen tissue of the original AD brain. They identified fungal proteins and DNA in the AD brain. No fungal DNA was identified in the brains of control subjects.

9 thoughts on “Fungi in the Alzheimer’s brain and changing views on amyloid beta

  1. H

    Very interesting. I wonder if the same process might be involved in the walls of blood vessels in CVD? I have seen it suggested that cholesterol plaques are a repair-mechanism.

    Reply
  2. Amy Proal Post author

    Hi H,

    I haven’t read any articles that suggest arterial plaque may be beneficial. Do you have a source for any possible articles?

    I can say that microbes probably play a large role in the creation of arterial plaque. That is because many studies now show that dead macrophages (immune cells) form the basis of arterial plaque.

    An increasing number of studies are also detecting various microbes in arterial plaque. See below for just two examples. This supports the possibility that the dead macrophages found in arterial plaque are killed by chronic infectious agents.

    http://mbio.asm.org/content/5/3/e01206-14

    http://www.ncbi.nlm.nih.gov/pubmed/15662025

    Cholesterol is typically thought to be the biggest problem in the creation of arterial plaque, but the above possibility challenges that assumption. If plaque accumulates more as a result of infectious processes, it could explain why lowering dietary cholesterol does not appear to help some patients with cardiovascular disease. A very good book to read to learn more about the relationship between dietary cholesterol and heart disease is “Good Calories, Bad Calories”, by Gary Taubes. Here on Amazon: http://www.amazon.com/Good-Calories-Bad-Controversial-Science/dp/1400033462/ref=sr_1_1?ie=UTF8&qid=1447874279&sr=8-1&keywords=good+calories+bad+calories

    Reply
  3. Rob Bermani

    Hi Amy,
    Insightful article. I heard about a paper published earlier this year in the journal Science Translational Medicine that found Scanning Ultrasound treatment to seemingly break up plaques and restore memory in transgenic mice designed to overly express Aβ. I don’t have a subscription so I couldn’t access the full paper. I understand there’s an argument that the mice are only an incomplete model of Alzheimer’s. However, it would seem plausible that the peptide could be beneficial in small amounts as a natural immune microbial defense but still harmful when produced systemically and unchecked. After all, these transgenic Alzheimer’s lab mice aren’t being infected with fungal or bacterial agents, but display the symptoms of Alzheimer’s dementia nevertheless. The peptide/plaque being harmful itself wouldn’t rule out an underlying fungal or bacterial etiology to the disease.

    paper:
    http://www.ncbi.nlm.nih.gov/pubmed/25761889

    Reply
    1. Amy Proal Post author

      Hi Rob,

      Thanks for your comment, and for sharing the link to the Science Translational Medicine article. I definitely take issue with the murine models used in the study. I have worked with mice in my career, and some of the best researchers I know work with mice. Nevertheless, if the microbiome plays even a small role in driving the pathogenesis of Alzheimer’s, the murine models in the paper you posted do not provide us with much reliable data.

      Differences in homology between humans and mice presents a big problem for medical research, IMO. For example, Seok and team at Stanford have published an excellent paper that shows vast differences in gene expression between mice and humans, in pathways that one might assume to be similar. In the next months I will write about the Seok paper in greater detail, but here is the link for now:

      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587220/

      I also discuss problems with murine/human homology in some of the research papers on this site. As I’ve written, “Men are not tall mice without tails”

      That being said, it’s entirely possible that amyloid beta may serve a protective role in Alzheimer’s at first, but than accumulate to a point where it becomes a problem as well. But I think we need more human data to explore that possibility.

      Best,

      Amy

      Reply
      1. Rob Bermani

        Thanks for the reply Amy, those are some great points. It’s exciting to think that some manifestations of Alzheimer’s may be curable or treatable in the future by more directly targeting an underlying opportunistic infection. Of course, it seems like there is still lots of research needed. Isn’t there evidence that some forms of Alzheimer’s are caused by deterministic gene variations (such as variations on amyloid precursor protein)? ie if you’ve inherited the variation, you’ll be guaranteed to have Alzheimer’s? I’d definitely be curious if the particular causative protein mutation results in an Amyloid Beta peptide that behaves as a less efficacious antimicrobial. That would lend further credence to the fungal etiology. I’ll look forward to reading your thoughts on the Seok paper 🙂

        Best,
        Rob

        Reply
  4. Amy Proal Post author

    Hi Rob,

    I did a quick literature search to better address your question. I came up with studies like that linked to below which claims: “Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). ”

    http://www.ncbi.nlm.nih.gov/pubmed/25531812

    A673T is a single nucleotide polymorphism. As you can see in this “basic concepts” article I wrote, I have some issues with SNPs:

    http://microbeminded.com/what-about-the-human-genome/

    That makes it hard for me to take a position on the role of gene variants in Alzheimer’s…

    Best,
    Amy

    Reply
    1. Rob Bermani

      Hi Amy,

      I’ve been in the process of relocating across the country, and I hadn’t time to reply. I was thinking about things more along the lines of autosomal-dominant Alzheimer’s disease, which I thought was a form of Alzheimer’s that was essentially guaranteed by genetics.

      Best Regards,
      Rob

      Reply
  5. Helen

    Another great post Amy!

    For me, the discovery that people with Alzheimers have obstructed jugular veins (CCSVI) is significant:
    http://www.buffalo.edu/news/releases/2013/11/036.html

    this narrows the list of candidate microbes playing a significant role in the diseases associated with obstructed jugulars, and thus may narrow the candidates playing a significant role in Alzheimers disease:
    http://www.abc.net.au/catalyst/stories/3572695.htm

    Interesting that the newly-discovered CNS lymphatic system also drains into the jugulars. It’s not hard to imagine that this could influence the build up of neurological artifacts in neurological diseases (amyloid plaque in AD, myelin in MS….):
    http://www.the-scientist.com/?articles.view/articleNo/43120/title/Brain-Drain/

    Interestingly, it’s been observed that higher loads of c.pneumoniae are found in people who have the APOE ε4 genetic variant commonly associated with Alzheimers:
    http://www.sciencedirect.com/science/article/pii/S0882401005000586

    Reply
    1. Amy Proal Post author

      Hi Helen,

      Interesting studies, thanks for sharing! Definitely looks like further research on obstructed jugular veins in Alzheimer’s is warranted. I also find it interesting that the CNS lymph system drains into the the jugulars. As far as candidate microbes in Alzheimer’s go – I think the door is still pretty open. So many microbes in the human body have yet to been fully identified and sequenced. We still need more data on the microbes that are able to persist in human blood.

      Best,
      Amy

      Reply

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