Alzheimer’s disease is the most common cause of dementia in older people. It has been actively studied for decades, but until now scientists have not been able to understand what causes Alzheimer’s disease. Recent work on another neurodegenerative disease, Parkinson’s disease, has shown that intestinal microflora may be involved in the pathogenesis. Researchers transplanted intestinal microflora from patients with Alzheimer’s disease into rats – and the recipient rats showed typical signs of this neurodegenerative disease: memory was impaired, and the formation of new neurons slowed down. Moreover, it turned out that, as in the work on Parkinson’s disease, the sulfate-reducing bacteria Desulfovibrio were “noted” here. The authors do not yet know what the role of these bacteria is and to what extent they are involved in general – this is the subject of further research.
Alzheimer’s disease – the most common reason dementia in old age. According to various estimates, 7–10% of people over 65 years of age suffer from dementia (S. Gale et al., 2018. Dementia) and, by according to WHO, 60–70% of them are caused by Alzheimer’s disease. These dry numbers mask the painful and terrifying symptoms that affect thousands of people around the world every year. First, a person begins to complain about poor memory, then he loses the ability to drive a car because he confuses road signs, then he stops recognizing his relatives and the way to his home. In the end, after years of illness, he will die from infectious complications in a state of severe dementia and complete loss of contact with reality.
The scariest thing about Alzheimer’s disease is the inevitability of this scenario. Some drugs help achieve short-term improvements in cognitive function, but they cannot stop the process of neuronal death that ultimately leads to neuronal loss. To slow it down, it is necessary to know the pathogenesis of the disease – the biological mechanism leading to the death of neurons. But it still remains unclear.
It has long been known that in Alzheimer’s disease, abnormal “balls” of protein form in the brain. APP (amyloid precursor protein – amyloid beta precursor). These deposits are called amyloid, and it was previously believed that they lead to the development of the disease. But the “amyloid” hypothesis was seriously shaken after systematic falsifications were found in a huge body of work on it (Systematic falsifications were found in articles on the mechanism of development of Alzheimer’s disease, “Elements”, 09.17.2022). And attempts to biochemically block the formation of amyloid have not yet been successful – blocking with antibodies simply did not lead to anything. This suggests that amyloid itself is not the triggering factor. But if not amyloid, then what?
Data on the pathogenesis of other neurodegenerative diseases, as well as experimental data on exactly how amyloid spreads and where it can arise, may provide interesting insights.
An earlier experiment in which mice were injected with amyloid into the intestinal mucosa showed that amyloid is able to travel from the intestines to the brain, most likely through fibers vagus nerve, which abundantly innervates the gastrointestinal tract (Mice were infected with Alzheimer’s disease through the intestines, “Elements”, 07/24/2020). Moreover, the experimental mice showed memory problems in behavioral tests – which clearly resembles human Alzheimer’s disease. The only problem is that no one injects amyloid into real patients, and even into the intestines. Therefore, the question remains unclear: if amyloid enters the brain through the intestines, how does it get there?
A related disease may shed light on this mystery. At Parkinson’s disease amyloid is also formed in the brain, only consisting of a different protein – alpha-synuclein (vinegar). A recent experiment showed that in this case, the process can begin in the intestines, and it has a specific culprit – sulfate-reducing bacteria of the genus Desulfovibrio (Fig. 1). A group of Finnish researchers isolated members of this genus from patients with Parkinson’s disease and from healthy volunteers, and then “fed” these bacteria to the tiny nematode Caenorhabditis elegans (Intestinal sulfate-reducing bacterium can transmit Parkinson’s disease from humans to nematodes, Elements, 06/02/2023). Nematodes that received bacteria from patients with Parkinson’s disease experienced increased deposition of amyloid in the head end (though not in the brain) and early mortality. Unfortunately, you can’t really track motor disorders on a nematode, and the authors of the work planned to repeat the experiment on a mammal—a mouse. “There are other animal models of Parkinson’s disease that are more human-like, such as mice.” — noted one of the co-authors Per-Erik Saris (Per-Erik Saris), answering questions from the author of the news. “Agents that caused alpha-synuclein aggregation in the worm also consistently caused alpha-synuclein aggregation in the mouse model. We are continuing experiments to analyze the effect of feeding model mice with Desulfovibrio strains from patients with Parkinson’s disease.”
While Saris’s group is planning such an experiment to study the pathogenesis of Parkinson’s disease, the journal Brain published article with a description of a similar study, but regarding Alzheimer’s disease – and not on mice, but on rats. Unlike Saris’s group, its authors did not isolate specific strains from patients with Alzheimer’s disease, but simply transplanted their entire intestinal microflora into rats (after killing their own with a cocktail of antibiotics). And the affected rats developed neurological disorders – at the cellular level, their neurogenesis, that is, the formation of new neurons, slowed down, and in behavioral tests they began to demonstrate memory problems.
The rats were forced to go through mazes of different designs, taught to recognize new objects and locations – and if the ability to run and swim was not affected, then the rats began to have obvious problems with remembering new places and objects. Everything looked like rats had suffered hippocampus – the part of the brain responsible for memory and affected in Alzheimer’s disease in humans (Fig. 2).
And what is most interesting is that in the microflora of patients with Alzheimer’s disease participating in the study, an increased proportion of bacteria of the genus Desulfovibrio was recorded. The same ones that, in a similar experiment, caused “Parkinson’s disease” in nematodes.
As a biorobot would say Werther from the movie “Guest from the Future”, “this is already a st-but-vit-sya in-te-res-but.” It turns out that sulfate-reducing vibrios can participate in the pathogenesis of two neurodegenerative diseases with different clinical picture and topic of damage, but united by common points in pathogenesis. Are they a universal “causative agent” of neurodegenerative diseases?
This is quite possible, but it should be noted that in the article discussed, the entire microflora was transplanted into rats, and we do not know for sure which of the many types of microbes included in its composition is associated with the occurrence of symptoms in rats. Moreover, other changes in the microbiota were observed in patients – in particular, the proportion of bacteria of the genus Coprococcus, for which a connection with good health in old age was previously described, was reduced (Fig. 3; T. Ghosh et al., 2022. The gut microbiome as a modulator of healthy ageing). So it’s difficult to answer the question: Are Desulfovibrio to blame for everything, or did the rats simply lack Coprococcus? Some third option is also possible, and even a combination of different effects from different bacteria.
So the treatment of Alzheimer’s disease with antibiotics is still a long way off – the circle of suspects is too wide.
Source: Stefanie Grabrucker, Moira Marizzoni, Edina Silajdžić, Nicola Lopizzo, Elisa Mombelli, Sarah Nicolas, Sebastian Dohm-Hansen, Catia Scassellati, Davide Vito Moretti, Melissa Rosa, Karina Hoffmann, John F. Cryan, Olivia F. O’Leary, Jane A. English, Aonghus Lavelle, Cora O’Neill, Sandrine Thuret, Annamaria Cattaneo, Yvonne M. Nolan. Microbiota from Alzheimer’s patients induce deficits in cognition and hippocampal neurogenesis // Brain. 2023. DOI: 10.1093/brain/awad303.
Georgy Kurakin
2023-11-02 14:53:03
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