The Brain Microbiome Project

For a long time, the brain has been considered an immune-privileged site, as it allows the entry of antigens without triggering the accompanying inflammatory response. The brain is protected from potential pathogens by a robust and near-hermetic blood-brain barrier. However, the presence of microbes is admitted in some pathological conditions, such as, Alzheimer’s disease, schizophrenia and meningitis. In the case of Alzheimer’s disease, accumulative evidence (since the 1970s) suggests that the formation of amyloid plaques is a response to infection. Amyloid beta shares similarities with antimicrobial peptides and is shown to protect against fungal and bacterial infections in nematode worms, laboratory mice, and cell cultures of human neuronal tissue. This highlights a neuroprotective role of amyloid beta accumulation and plaque formation, which is known to trigger neuro-inflammation and cell death at later stages of the disease.

The Brain Microbiome Project, led by Robert Moir and Rudolph Tanzi (Harvard University) aims at mapping the microbiome that exists in the brains of Alzheimer’s disease patients and determining which component of the microbiome is ‘’leaking’’ in the brain. In earlier studies, they showed amyloid beta to be an antimicrobial peptide, used by the immune system of the brain, to fend off infection. In the long-term, this could enable the development of new therapeutic strategies focussing on the brain microbiome, to decrease amyloid beta accumulation.

The presence of microbes in the brain has long been considered a sign of disease. Interestingly, conflicting data, announced during the annual Society for Neuroscience meeting held in San Diego last year claims that there are bacteria in the healthy brain. Rosalinda Roberts (Alabama University) showed pictures of non-pathogenic bacteria in brain cells, mostly in astrocytes and in myelinated axons. This was a serendipitous discovery and is yet to be published. When Roberts’ team was comparing the brain anatomy of deceased people with schizophrenia to healthy controls, they always found the same strange structure: bacteria! One could argue that this could be from post-mortem contamination, since brains are not protected just after death and bacteria can proliferate in dead tissue. To rule out this possibility, Roberts’ lab reproduced the experiments in mice and found that bacteria could also be detected in their brains, which were harvested right after death. They also used germ-free mice; devoid of normal intestinal microflora and living in sterile conditions. They found no bacteria in the brains of these mice,  proving that contamination during tissue preparation was not the source of bacteria in the brain. In addition, the bacteria were abundant in particular brain structures; the hippocampus, substantia nigra and prefrontal cortex. If a contamination was involved, it would not show such a specific pattern of infection.

Why have bacteria not been observed in the brain before? The brain has been under investigation for such a long time that it seems difficult to believe that such a seemingly glaring observation was not made earlier! To this question, Rosalinda Roberts said that when one is studying something specific and doesn’t expect to see something (in this case, bacteria), one is likely to overlook them. She states that since she showed the images at SFN, she has been contacted by other researchers who also saw bacteria in the brains they were studying! They simply had no idea what they were looking at until Roberts’ interesting discovery.

The majority of these brain resident bacteria are similar to intestinal bacteria, suggesting that they could originate in the intestine and travel to the brain through nerve fibers and/or blood vessels (considering that the blood-brain barrier is leaky at certain sites). Another possibility could be that lymphocytes, cells that can pass the blood-brain barrier, phagocytosed the bacteria without killing them and then entered the brain parenchyma. Recent advances in research on the gut-brain axis could help tie these phenomena together.

This fascinating discovery has opened the door to a plethora of questions. What do these bacteria do in the brain? Are there good and bad bacteria? Would balancing their effect influence the development of neuropathologies? A whole new field waits to be explored!

Rosalinda Roberts’ poster abstract at SfN 2018:  https://abstractsonline.com/pp8/#!/4649/presentation/32057

 

Written by Isabelle Arnoux; Edited by Radhika Menon. Design by NGC/Carine Thalman.

Resources:

https://news.harvard.edu/gazette/story/2017/05/devastating-chain-of-events-found-in-alzheimers-path/