Brain Infections Help Us Understand What Causes Alzheimer‘s Disease

Shin

Will antimicrobials be the future treatment for Alzheimer’s?

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Classic AD Etiology: Amyloid Cascade

Alzheimer’s Disease (AD) is the most common type of neurodegenerative disease. Its prevalence can only increase as the aging population continues to increase too, owing to improving healthcare. For many decades, the infamous etiology for Alzheimer’s disease (AD) is the “amyloid cascade hypothesis” wherein misfolded amyloid-beta peptides accumulate in the brain. This forms amyloid plaques that disrupt functions of neurons and trigger chronic neuroinflammation — leading to AD [1].

Inflammation: recruitment of immune cells that release toxic (and inflammatory) chemicals that damage targeted cells (e.g., virus-infected cells or bacterial cells).

Chronic inflammation: when inflammation is not halted or properly regulated which, thus, damages nearby (bystander) normal cells — an acknowledged root cause of many diseases.

Today, treatments and interventions based on the “amyloid cascade hypothesis” have been disappointing. None of the dugs targetting amyloid-beta peptides passed clinical trials. This is not because the hypothesis is false, but rather it is unclear what initiated the formation of amyloid-beta peptides in AD, to begin with [2].

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Novel AD Etiology I: Microbial Infection

In a symposium held in 2017 [3], renowned speakers conveyed their research supporting the causal roles of microbes in the development of AD:

  • Professor Ruth Itzhaki on HSV-1 and AD
  • Dr Judith Miklossy on spirochetes (Treponema pallidum) and AD
  • Professor Brian Balin on Chlamydia pneumoniae and AD

These three microbes have been extensively researched and, thus, being the main highlights being showcased in the symposium [3]. These pathogenic microbes can induce neuropathological hallmarks of AD — such as amyloid plaques and tangles — via a variety of mechanisms. However, many other microbes have been associated with AD, but with comparably less research being done on them [4]. This list of AD-related microbes are illustrated herein:

https://img.particlenews.com/image.php?url=2oRNiN_0Z1tEBkM00* Image from the author: List of different microbes that have been associated with AD.

Novel AD Etiology II: Antimicrobial Protection

Back to basics: What are the functions of amyloid-beta peptides? Aside from hindering routine neuronal activities, it also serves as an antimicrobial peptide! [5–7] That surprised many academicians. An obvious logic here is that amyloid-beta peptides form and accumulate over the years as a result of persistent or continuous microbial infections in the brain [2].

Antimicrobial peptides: the first line of defense against microbial infections; common types include defensins, cathelicidin, and lactoferrin that are secreted by innate immune cells.

No wonder AD is an age-related disease. No wonder herpes simplex virus type 1 (HSV-1) has been recognized as a highly likely etiological agent in AD as HSV-1 is included in the antimicrobial spectrum of amyloid-beta peptides [4,5].

AD Etiology Refined

By looking at AD from a different biochemical perspective, that is with the involvement of antimicrobial peptides, existing theories are beautifully synthesized. Unbeknownst to us, our immune system deploys antimicrobial peptides in response to the constant, never-ending battle with pathogenic microbes. Alzheimer's disease may be an unfortunate casualty of this if the antimicrobial peptides — microbes crossfire takes place in the brain.

“Research data on a microbial cause of AD have been ignored or dismissed for three decades, very unfortunately for those who developed AD during that period and who therefore had no chance of benefitting from the information,” writes Ruth Itzhaki, Professor Emeritus of Molecular Neurobiology [8].

Even though Prof. Itzhaki’s applications for funding to conduct AD clinical trials based on antivirals have been denied many times, research can only move forward. “Now is the time to rectify the situation by determining and then using the best means of treatment at hand,” Prof. Itzhaki further commented.

The Future Treatment

Diverse microbes — bacteria, viruses, fungi, protozoa — are contributive to AD. Microbes have co-evolved with complex eukaryotes like humans, either for the better (symbiosis) or worse (dysbiosis/adversaries). Can fighting these adversaries with antimicrobials prevent the formation of amyloid-beta plaques and, thus, prevent/treat AD?

In a nationwide, population study that successfully reduced the risk of developing AD by 90% with antiherpetic drugs [9]. Furthermore, a clinical trial is currently assessing the efficacy of valacyclovir (an antiherpetic drug) in preventing the development of AD (ClinicalTrials.gov ID: NCT03282916).

A pilot study in 2019 administered lactoferrin — an antimicrobial peptide commonly present in our body — to AD patients. Treatment outcomes were remarkable with the AD patients showing improved cognitive functioning and decreased blood levels of amyloid-beta peptides and other oxidative and inflammatory biomarkers [10].

Could future therapy for AD be based on antimicrobials? Or detecting prior microbial exposures and, consequently, design suitable medical intervention(s)? Indeed, interventions based on a firmly-grounded etiological basis should work.

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References

  1. Jack et al. (2010). Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade.
  2. Weiling et al. (2014). Potential role of antimicrobial peptides in the early onset of Alzheimer’s disease.
  3. Fulop, T et al. (2018). Role of Microbes in the Development of Alzheimer’s Disease: State of the Art — An International Symposium Presented at the 2017 IAGG Congress in San Francisco.
  4. Ashraf et al. (2018). The Possibility of an Infectious Etiology of Alzheimer Disease.
  5. Soscia et al. (2010). The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide.
  6. Bourgade et al. (2015). beta-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1.
  7. Bourgade, K., Le Page, A., Bocti, C., Witkowski, J.M., Dupuis, G., Frost, E.H., et al. (2016). Protective Effect of Amyloid-beta Peptides Against Herpes Simplex Virus-1 Infection in a Neuronal Cell Culture Model.
  8. Itzhaki, R.F. (2018). Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer’s Disease.
  9. Tzeng et al. (2018). Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections-a Nationwide, Population-Based Cohort Study in Taiwan.
  10. Mohamed et al. (2019). A pilot study on the effect of lactoferrin on Alzheimer’s disease pathological sequelae: Impact of the p-Akt/PTEN pathway

* This article was originally published here with modifications.

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