The field of Alzheimer's disease research is in the midst of a slow-moving and consequential debate over the role of infection in the development of the condition. The fundamental question is this: in the absence of genetic variants that raise risk, why do only some people progress to full blown Alzheimer's disease? The presence - in only some people - of sufficient degrees of persistent infection is one possible answer to that question. Candidates include herpesviruses, oral bacteria such as P. gingivalis, lyme disease spirochetes, and others.
Alzheimer's is a condition characterized by amyloid-β aggregation in its early stages and tau aggregation in its later, more severe stages. The classic amyloid cascade view of the condition is that amyloid-β aggregation sets the stage for immune dysfunction and chronic inflammation leading to tau aggregation. The debate over whether or not persistent infection instead lies at the root of the condition has so far largely focused firstly on amyloid-β as an anti-microbial peptide, a part of the innate immune system that may be upregulated by infection, and secondly on the chronic inflammation that results from infection, as inflammation in the brain clearly strongly drives tau pathology.
Here, however, researchers offer evidence for the presence of bacterial DNA to accelerate the processes of tau aggregation through mechanisms independent of inflammation. Some forms of bacterial DNA may help to seed the aggregates of tau that can then spread independently. The challenge will be, as ever, to determine which of these various processes is the important one, which has the larger contribution. That is hard to accomplish without selectively blocking each disease process in isolation and observing the results.
In addition to being one of the most devastating diseases of the 21st century, Alzheimer's disease (AD) remains incurable. The cognitive symptoms and neurodegeneration appear to be mostly related to the extensive synaptic dysfunction and neuronal death observed in the brain. In turn, neuronal loss and synaptic damage appears to be mediated by the progressive misfolding, aggregation, and deposition of amyloid-β (Aβ) and tau proteins forming protein aggregates able to spread from cell-to-cell by a prion-like mechanism. Genetics alone cannot account for the complex process of protein misfolding, aggregation and subsequent neurodegeneration observed in AD, particularly because the large majority of the cases are not associated to genetic mutations. Thus, it is likely that diverse environmental factors and age-related abnormalities play an important role on the initiation of the pathological abnormalities. In this sense, various studies have shown that bacterial infection, as well as alterations in the intestinal microbiome may be implicated in the AD pathology.
Here, we report the first evidence for the capacity of extracellular DNA from certain bacterial species to substantially promote tau misfolding and aggregation. The promoting effect of DNA on tau aggregation was observed in a wide range of concentrations from 10 to 1000 ng. The use of these concentrations were informed by the range of cerebrospinal fluid DNA concentrations observed in patients with different diseases: 1-600 ng/mL. The sources of bacterial and fungal DNA were selected based on the literature and personal data that showed associations of certain microorganisms with AD. Among the bacteria previously cultivated directly from the brains of patients with AD, or those whose components (such as nucleic acids, lipopolysaccharides, enzymes) were identified in the cerebrospinal fluid, amyloid plaques, or brains of patients with AD, we used the DNA from B. burgdorferi, P. gingivalis, C. albicans, and E. coli.
Our data indicate that DNA from various, unrelated gram-positive and gram-negative bacteria significantly accelerated Tau aggregation. One of the best promoters was DNA from E. coli species, which is interesting for several reasons. First, it was demonstrated that some strains of E. coli were detectable immunocytochemically in brain parenchyma and vessels in AD patients more frequently compared to control brains. Second, E. coli and P. gingivalis are known to share properties of facultative intracellular parasites and be localized within hippocampal neurons; the latter finding is significant, as the hippocampus is extensively damaged in AD. The intracellular localization of E. coli introduces unique possibilities regarding the interaction of bacterial DNA with tau proteins inside the neuron; e.g. DNA can be secreted via transportation to the outer membrane or released following prophage induction and directly access the host neuron's cytosol, where tau is normally present. Of note, in brains of patients with AD, P. gingivalis is also localized intracellularly; therefore, as in the case of E. coli the same processes for the intracellular interaction of its DNA with tau are applicable for this microorganism.
Future studies should further investigate the possible role of DNA as an initial seeding factor for protein misfolding using cellular and in vivo models as well as the effect of DNA on inducing misfolding of other proteins, including those associated with neurodegeneration, autoimmune diseases, and cancer. Moreover, subsequent studies should explore the targeting of DNA as a therapeutic strategy to prevent tau aggregation.