[Neurosciences] Gutting out the brain: recents studies highlight a contribution of gut microbiota into the pathogenesis of Alzheimer’s and Parkinson’s disease

If there are some neurological diseases that almost everyone know about, it is certainly neurodegenerative diseases such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (aka Lou Gehrig’s disease), Huntington’s disease (HD) or Parkinson’s disease (PD) for two major reasons: first they are neurodegenerative diseases (that means patients are loosing a particular type of neurons) and incurable (there is no cure to reverse the condition and there is no treatment available to stop the progression). With such diseases, the outcome is grim.
What is interesting with several of these diseases is the formation of protein aggregates or “clumps”. These “clumps” are either due to some mutation in the gene (this is the case of hungtintin and its mutated pathogenic form in HD), formation of protein byproducts (Abeta peptides formed by the cleavage of the amyloid precursor protein by beta-secretase in AD) or yet known exactly known (alpha-synuclein in PD).
In the case of AD, the presence of amyloid plaques (rich in Abeta clumps) and tangles in patients brain was the hallmark pathological feature described by Alois Alzheimer over an 100 years ago. Thus the formation of these Abeta clumps and plaques were seen as the main culprit in the progression of the disease and therefore the main target. A lot of research has been done, clinical trials have been set following promising results in animal models to reduce such plaques formation only to fail miserably in Phase II and III clinical trial (see the recent failure of Lilly’s drug candidate for fighting AD Abeta plaques).
However, some scientists suggested that Abeta plaques were possibly just a consequence of something else preceding. For them the Abeta is considered as a defense to some pathogens, as Abeta peptides have been reported carrying some antimicrobial activity.
In the recent years,  a particular attention has been raised on the gut microbiota and the presence of a “gut-brain axis” involving a possible reciprocal cross-talk between these distant organs.
Two studies published recently brings more information of the contribution of an altered gut-brain axis. One from Frank Sharp (MD) and colleagues from UC-Davis and published recently in Neurology (http://www.neurology.org/content/87/22/2324.full) documented the presence of lipopolysaccharides (LPS), a marker of Gram-negative bacteria and K99 antigen from Escherischia coli (a Gram-negative bacteria commonly found in the mammalian gut and a classical pathogen involved in food poisoning) in brain parenchyma and around vessels. These antigens were also co-localizing Abeta peptide 1-40 and 1-42. We don’t know if this microorganisms can induce Alzheimer’s but it seems that such co-localization suggests some sort of restraining and confinement of the pathogen spreading.
The second one, from Sarkis Mazmanian (PhD) and colleagues from CalTech and published in Cell (http://www.cell.com/cell/abstract/S0092-8674(16)31590-2). Using mice over expressing alpha-synuclein (aSyn), the authors observed that gut microbiota was promoting the onset and progression of aSyn in the brain. This finding is interesting because it matches with another ongoing study presented at the recent annual meeting of the Society of Neurosciences (SfN) that i attended that claimed that aSyn deposition started first in the gut before taking place in the brain. They also found that erasing the gut microbiota was improving the outcome in mice compared to non-treated mice and that treatment of mice with metabolites produced by these bacteria (think about some sort of apple cider juice) resulted in similar effects. In contrast to the first study, this second one show that just metabolites was triggering brain inflammation via microglial cells activation.
It is very interesting to see how the science in these two diseases unfold and for me, it is interesting to see how these metabolites interact with the BBB. Do they passively diffuse? Do they have some transporters? Do aSyn hops from the gut and squeeze into the brain? A lot of questions remains unanswered and again more studies are needed.
Source for the news: www.neurosciencesnews.com


2 thoughts on “[Neurosciences] Gutting out the brain: recents studies highlight a contribution of gut microbiota into the pathogenesis of Alzheimer’s and Parkinson’s disease

    • Exactly! My question I have about this axis are:
      1. What kind of metabolites are crossing the gut barrier?
      2. How these metabolites enter the BBB and get cleared out?
      The first question may come in next-generation sequencing and fancy metabolomics studies (thats surely some exciting stuff for chemists with their mass spec).
      The second question I have is about the fate of these metabolites once they cross the BBB. Is there any brain metabolism that inactivate these metabolites, even at the BBB? Does the glymphatic system provide a bulk flow that brings these metabolites back into the circulatory system and clear them via the liver and kidneys?
      Human anatomy (and physiology) is weird but very fascinating.


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