Many neurological conditions are characterized by the formation of proteins or “plaque” in brain tissue. Two such proteins are amyloid beta and prion protein (PrP). Amyloid beta forms the “plaque” associated with Alzheimer’s disease. PrP has been detected in the brain/nervous system of patients with Parkinson’s Disease, schizophrenia, bipolar disorder, and even major depression.
Most of the scientific community currently regards both amyloid beta and PrP as drivers of neurological inflammation and disease. In Alzheimer’s, amyloid beta “plaque” is believed to be a useless substance that promotes symptoms and degeneration. PrP is best known for its association with Mad Cow Disease. In Mad Cow Disease and related “prion disorders” PrP protein is believed to fold incorrectly. This “misfolding” allows PrP to better access brain tissue, where it is also believed to cause symptoms and dysfunction.
However, several recent studies by researchers at Massachusetts General Hospital (Harvard) and Lund University Sweden challenge the above assumptions. In fact, their groundbreaking research calls for a complete re-evaluation of the role amyloid beta and PrP play in neurological disease. The Harvard/Lund studies demonstrate that both amyloid beta and PrP have a previously undiscovered function: they are potent antimicrobial peptides. Antimicrobial peptides are natural, broad spectrum antibiotics created by the body that destroy bacteria, enveloped viruses, fungi and even transformed or cancerous cells.
How does this change the game? If amyloid beta and PrP are antimicrobial peptides, they serve a protective role in patients with Alzheimer’s, Parkinson’s, and other conditions. Both proteins almost certainly form as part of the immune system’s response to infection in patients with these conditions.
Amyloid beta’s potent antimicrobial activity was first characterized by Moir and team at Massachusetts General Hospital. In 2009 they reported 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: the leading cause of bacterial meningitis.
The pathogen that Moir and team identified as being most sensitive to amyloid beta is the fungus Candida albicans. Indeed, Moir 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.
In a second 2016 study, Moir and team showed that amyloid beta protects against fungal and bacterial infections in mouse, nematode, and cell culture models of Alzheimer’s disease. In fact, when mouse brains were infected with the bacteria Salmonella Typhimurium, amyloid beta formed rapidly in response to the infection (with amyloid beta deposits closely associated with invading bacteria)
The team concluded:
..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.
Around same time that Moir and team characterized amyloid beta’s antimicrobial activity, a Swedish team at Lund University reported that PrP protein is also an antimicrobial peptide. The team found that synthetic PrP peptides killed the bacterial species Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. PrP also displayed potent antimicrobial activity against the fungus Candida parapsilosis.
The team further reported that PrP “breaks up” microbial membranes in a fashion similar to “classical” human antimicrobial peptide LL-37. They also showed that PrP is created as a response to wound healing in human skin. Indeed, in human skin cells, PrP protein induced production of TGF-α, a cytokine the body creates to target infectious agents.
Other independent studies support PrP’s role as an antimicrobial peptide. A team in Germany found that PrP expression was increased in patients with H pylori-infection, and not in non-infected controls. PrP levels decreased to normal after successful eradication of the H pylori bacteria. The team concluded that, “H pylori creates a milieu for enhanced propagation of prions in the gastrointestinal tract.”
Another study demonstrated PrP formation in skin cells removed from patients with psoriasis, contact dermatitis, squamous cell carcinomas, and viral warts (conditions tied to infection/skin microbiome imbalance). In these skins cells, cytokines associated with a response towards infection increased PrP production. A different team found that sheep with scrapie (an infectious condition) and lentiviral mastitis secrete prions into their milk (these prions were not created in sheep without the viral infections).
Alpha-SYN production is also promoted by toxic insult, local inflammation, and oxidative stress: conditions all associated with the presence of chronic infection.
PrP’s ability to act as an antimicrobial peptide is particularly relevant in light of research connecting Parkinson’s Disease to prion creation. This October, the Journal of Neuroscience published two articles implicating alpha-SYN (a form of PrP) in Parkinson’s Disease. While this association between alpha-SYN and Parkinson’s has been reported for decades, the papers clarify the latest thinking on the topic. The authors of each paper debate details of how alpha-SYN accumulates in the Parkinson’s brain, but both conclude with a common belief: alpha-SYN proteins CAUSE or drive Parkinson’s disease progression.
Key to the above assumption is that both research teams do not appear to have read the Lund University study showing that PrP is an antimicrobial peptide. Or if they have, they didn’t cite the paper in their references, or refer to the findings anywhere in their writing.
This is a major problem, because just like in Alzheimer’s, alpha-SYN is very likely not causing PD, but is instead accumulating in response to an as yet uncharacterized infection, or communities of infectious agents. In fact, the discovery that amyloid beta and PrP are antimicrobial peptides IS A GIANT CLUE suggesting that infectious agents in the brain are contributing to both disease states.
What infectious agents might these be? There are many possibilities. Researchers at the University of Alberta recently detected an ecosystem of chronic microbes in the autopsied brains of patients with HIV and a range of other medical conditions associated with severe neurological dysfunction. They detected 173 bacteria and bacteriophage-derived samples. Many of these microbes were identified inside macrophages, astrocytes, microglia, and other cells of the immune system.
Several microbes identified in the brains were pathogens associated with specific human diseases. They included Delfia acidovorans, a pathogen implicated in endocarditis, bacteremia, and urinary tract infections. Delfia acidovorans has even been identified as part of the bacterial community in the arterial wall of patients who have aortic aneurysms. Viruses (including various herpes viruses) were also identified in many of the brain samples.
Another study by researchers a the Universidad Autónoma de Madrid studied the brains of patients with Alzheimer’s. All eleven Alzheimer’s brains studied were infected with a range of fungal organisms.
These preliminary findings suggest that we should greatly prioritize new studies that search for microbes in brain tissue and the central nervous system. If more microbes are identified, the data may transform current models of Alzheimer’s, Parkinson’s and other neurological conditions.
Progress in this area is stymied by the fact that most members of the scientific/medical communities are not aware of the findings discussed in this post (amyloid beta and PrP’s antimicrobial activity and/or the latest studies on microbes in the brain).
This may explain why, since 2002, 400 Alzheimer’s drug trials have been run and all 400 have failed. Many of these drugs have attempted to remove amyloid beta from the Alzheimer’s brain. But if amyloid beta is an antimicrobial peptide such treatments are removing a result of the disease process rather than the cause. No wonder they don’t work!
Meanwhile, Alzheimer’s disease is the sixth leading cause of death in the USA, with a new case diagnosed every 66 seconds. Without treatment, these numbers are predicted to explode to 16 million Americans with the disease, at a cost of over $1 trillion dollars by 2050. Then, factor in patients with Parkinson’s, schizophrenia, and other conditions tied to PrP and the impact of the discoveries described in this post is TREMENDOUS.
For example, Bill Gates just announced a new mission: He is investing $50 million of his own money into the Dementia Discovery Fund, a private-public research partnership focused on Alzheimer’s research. However, the research teams he is funding do not seem aware of Moir and team’s findings on amyloid beta and/or the paradigm shift in Alzheimer’s research that the discovery warrants.
We cannot pour this kind of money into research going in the wrong direction. There is too much suffering, too much debilitation, and far too great a cost to society. Please, if this post speaks to you, share it with as many members of the medical community as possible.
Note: It’s possible that amyloid beta and PrP play a “dual role” in chronic disease. They may combat infection initially, but cause problems if their levels become very high. For example, Moir and team point out that LL-37 (the most well-studied human antimicrobial peptide) can become cytotoxic to host cells at very high concentrations.
A final consideration: could prions (PrP) play a role in ME/CFS?
In 2008 I watched prion researcher Adrianno Aguzzi speak at the “Days of Molecular Medicine Conference” in Karolinska Sweden. His team reported that activated B lymphocytes play a critical role in facilitating prion formation.
Norwegian researchers have reported that the immunosuppressive medication ritauximab can alleviate ME/CFS symptoms. Rituximab “knocks out” B lymphocytes. If prions play a protective role in ME/CFS, their inability to form in the presence of Ritauximab would decrease patients’ ability to fight infectious agents. This would result in decreased immunopathology (less of a battle between immune cells and microbes). Inflammation and symptoms would subsequently drop, although infectious agents driving the disease would be able to spread with greater ease.