The Pathway to Alzheimer’s Disease from Spirochetes to Amyloid-β

Recently, Miklossy has shown Borrelia cultured from brains of Alzheimer’s disease (AD) not only grew organisms, but those organisms made biofilms, amyloid-β protein precursor (AβPP), and amyloid-β (Aβ) in vitro as well [1]. With that observation, the major events in the pathogenesis of this dreaded disease have been made much clearer. They (major events) originate in most cases of the disease with spirochetes; Aβ, which is a constant in the disease, assumes a lesser role. This concept fits well with the original thought of Alzheimer himself that the disease bearing his name began with a microbe [2].

Similar to syphilis (which is an exact comparator to AD), AD begins with spirochetes arriving at the brain [3]. In syphilis, the spirochetes travel to the brain, most likely during the secondary stage when there is bacteremia. In AD, they either travel to the brain after an Ixodes tick bite during the secondary stage of Lyme disease or during dental surgery, when oral spirochetes become bacteremic [4]. The hippocampus, a favored area of involvement in AD, is approximately 4 cm from the posterior oral cavity, and frequently the return venous flow from the mouth is through that cerebral region (cavernous sinus). The percentage of spirochetes involved in that landmark study was 25% Lyme and 75% dental [5].

Once in the brain, the spirochetes divide, multiply, and form biofilms. This process takes many years in developing (multiple decades) because the microbes divide so slowly. They need to build up a population density such that a “quorum” is achieved, and then they begin to spin out a biofilm (slime) to protect themselves [6]. There are many provoking factors such as temperature, low dose antibiotics, etc., but “quorum sensing” seems the most likely in this instance.

The biofilm is composed of spirochetes, extracellular polysaccharides, DNA, amyloid, fatty acids, protein, dead cells, exporter cells, and water channels. Most organisms can make biofilms as has been shown in atopic dermatitis with staphylococci [7], psoriasis with streptococci [8], and tinea versicolor with Malassezia furfur/ovale [9]. Once made, the biofilm is impenetrable, especially as regards ordinary antibiotics and the immune system (both arms).

The next occurrence in AD is the activation of the innate immune system. Toll-like receptor 2 (TLR2) is upregulated and is attracted to the spirochetes encased in slime. TLR2 may be drawn to the biofilm by “curli” fibers as has been previously described [10]. In its ordinary role, TLR2 kills organisms by coating the pathogens and destroying them with tumor necrosis factor α (TNFα) that arises from the myeloid differentiation 88 (MyD88) pathway. (This pathway is also used by TLR4.) The postulate is that, inasmuch as TLR2 cannot penetrate the biofilm, its activation and TNFα destroy the surrounding tissue instead [4]. In the aforementioned atopic dermatitis and psoriasis, TLR2 cannot kill the offending microbes because of the biofilm, and leads to the generation of those diseases.

A further step in the pathogenesis is the formation of Aβ. This has been shown most likely to be a result of the activation of the MyD88 pathway from TLR2. Nuclear factor kappa B (NFκB) arises from that pathway also, and in the presence of Aβ converting enzyme catalyzes the production of β-secretase and γ-secretase which both give rise to Aβ upon cleaving AβPP. (The γ-secretase is seen in the genetic form of the disease associated with the APOE ε4 gene.) The Aβ is antimicrobial, and it attacks the spirochetes in the biofilm, but cannot penetrate just as the TLR2 cannot. It coats the biofilm, and its buildup destroys the neurocircuitry irrevocably [6].

Miklossy’s recent observation explains how the AβPP gets where it is: the spirochetes make it. If it is enclosed in the biofilm, it could act like infrastructure for the biofilm as ordinary amyloid does in other diseases. If it remains outside the biofilm, it can be converted to Aβ by the β-secretase as previously mentioned. Any Aβ that is also made by the spirochetes would function as above and coat the biofilms and degrade the neurocircuits.

A word about treatment: as has been stated previously, it is important to kill the spirochetes before they arrive at the brain or before they do damage (make biofilms) [6]. As in syphilis, a bactericidal antibiotic is most important and the protocol has been recently outlined. Tertiary syphilis has been eradicated by such a course of treatment. Conceivably, tertiary spirochetosis (AD) can be similarly eradicated.

After AD has begun, it may be possible to arrest the damage, but whatever neurodamage that has been created, cannot be undone. There is promise in the form of a microarray blood study that recognized 100% of early AD [11]. Perhaps that protocol could be “fine-tuned” to identify changes in AD in the “latent” stage, similar to the RPR identifying active spirochetal involvement in syphilis.

Herbert B. Allen, Jennifer R. DiBiagio, Suresh G. Joshi
Drexel University College of Medicine, Philadelphia, PA, USA. E-mail: Herbert.Allen@drexelmed.edu

References
[1] Miklossy J (2016) Bacterial amyloid and DNA are important constituents of senile plaques: further evidence of the spirochetal and biofilm nature of senile plaques. J Alzheimers Dis 53, 1459-1473.
[2] Alzheimer A as referenced in Miklossy J (2015) Historic evidence to support a causal relationship between spirochetal infections and Alzheimer’s disease. Front Aging Neurosci 7, 46.
[3] Miklossy J (2011) Alzheimer’s disease – a neurospirochetosis. Analysis of the evidence following Koch’s and Hill’s criteria. J Neuroinflammation 8, 90.
[4] Allen HB, Morales D, Jones K, Joshi S (2016) Alzheimer’s disease: A novel hypothesis integrating spirochetes, biofilm and the immune system. J Neuroinfect Dis 7, 1.
[5] Riviere GR, Riviere GH, Smith KS (2002) Molecular and immunological evidence of oral treponemes in the human brain and their association with Alzheimer’s disease. Oral Microbiol Immunol 17, 113-118.
[6] Allen HB (2016) Alzheimer’s disease: assessing the role of spirochetes, biofilms, the immune system, and amyloid-beta with regard to potential treatment and prevention. J Alzheimers Dis 53, 1271-1276.
[7] Allen HB, Vaze ND, Choi C, Hailu T, Tulbert BH, Cusack CA, Joshi SG (2014) The presence and impact of biofilm-producing staphylococci in atopic dermatitis. JAMA Dermatol 150, 260-265.
[8] Allen HB, Neidig L, Zhang J, Shave C, Cusack C (2015) The etiology of psoriasis: Its close association to streptococcus. J Am Acad Dermatol 72, AB254.
[9] Allen HB, Goyal K, Ogrich L, Joshi S (2015) Biofilm formation by Malassezia furfur/ovale as a possible mechanism of pathogenesis in Tinea versicolor. J Clin Exp Dermatol Res 6, 311.
[10] Tukel C, Wilson RP, Nishimori M, Pezeshki M, Chromy BA, Baumier AG (2009) Responses to amyloids of microbial and host origin are mediated through toll-like receptor 2. Cell Host Microbe 6, 45-53.
[11] DeMarshall CA, Nagele EP, Sarkar A, Acharya NK, Godsey G, Goldwaser EL, Kosciuk M, Thayasivam U, Han M, Belinka B, Nagele R (2016) Detection of Alzheimer’s disease at mild cognitive impairment and disease progression using autoantibodies as blood biomarkers. Alzheimers Dement (Amst) 3, 51-62.