Intestines and Alzheimer's disease
Mice were infected with Alzheimer's disease through the intestines
Polina Loseva, "Elements"
Alzheimer's disease is the most common neurodegenerative disease. There is no cure for it, and, moreover, scientists do not yet know even reliable markers of this disease that allow diagnosing it before the first symptoms appear, because in order to identify the main symptom of Alzheimer's disease – beta-amyloid plaques – it is necessary to examine brain tissue. But if the disease does not start in the brain, but somewhere else, then doctors will have the opportunity to notice it in the early stages and prevent progression. A potential opportunity for this was established by scientists from Hong Kong. In a recent study on mice, they found that beta-amyloid aggregates injected into the intestinal wall are able to penetrate the brain. However, it is still unclear whether this is the only way and whether it is actually used.
Fig. 1. Accumulation of beta-amyloid in the vagus nerve of mice. Different parts of the nerve are colored with different dyes: blue – the nuclei of neurons, green – the processes of neurons, red – beta-amyloid molecules. A – mice from the control group, B – mice who received an injection of saline, C and D – mice who received an injection of beta-amyloid into the intestine. The length of the scale segments is 20 microns. An image from a discussed article in The Journal of Physiology.
Alzheimer's disease, like many other neurodegenerative diseases, is an "epidemic" that affects the brain, gradually spreading through the nervous tissue. It begins, as a rule, in the hippocampus and the cerebral cortex. Therefore, one of the first symptoms of the disease are memory problems. Then it moves through the brain, capturing the thalamus, the midbrain and, finally, the cerebellum, leading to a violation of cognitive and motor functions.
The driving force of the "epidemic" is the peptide beta-amyloid (Aß) – a fragment of the membrane protein ARP, which is cleaved from the surface of neurons. Some Aß molecules take an irregular shape, and "sticky" hydrophobic areas protrude on their surface. Such improperly folded molecules become "seeds" – the nucleus for the future protein lump. Sticking together into insoluble aggregates, they simultaneously force other Aß molecules to take a distorted shape, and so the lump increases and grows like a snowball. In the end, it takes the form of an amyloid plaque (Fig. 2) – an extracellular accumulation of proteins, by which the pathologist identifies traces of Alzheimer's disease in the tissue. As a result, the surrounding cells are under a double blow: in addition to the fact that amyloid itself can be toxic to neurons, plaques destroy the connections between them and interfere with the transport of substances inside the tissue.
Fig. 2. Beta-amyloid plaques (large pink spots) in the brain of a patient with Alzheimer's disease. Image from the website commons.wikimedia.org .
Despite the fact that beta-amyloid aggregates are considered the main sign of Alzheimer's disease, and their accumulation is one of its main causes, no therapy based on their destruction has yet been successful. At the time of writing this text, most of the world's largest pharmaceutical companies have closed the development of drugs for Alzheimer's disease (only Biogen remains afloat, but the data from its latest clinical trials are also questionable).
What is the reason for these failures is still unclear. Perhaps the initial premise is incorrect, and amyloid plaques are a false target, that is, they are not the cause of the disease, but its symptom. But maybe it's just that we are trying to intervene in the process too late, when the beta-amyloid "snowball" has already started traveling through the brain tissue, plaques are forming, and the destruction of individual "snowflakes" can neither stop the "epidemic" nor reverse neurodegeneration. In this case, you need to learn to recognize the symptoms of the disease before they become irreversible. And since it is difficult to analyze brain tissue in a living person, markers of the early stages of Alzheimer's disease are searched for in more easily accessible parts of the body, for example, in blood, eyes or cerebrospinal fluid – also, however, so far in vain.
But what if the "epidemic" begins not in the brain, but in some other organ? The brain is not a closed system, it can be accessed in a variety of ways: for example, through the hemato–encephalic barrier or through incoming nerve fibers. If it were possible to find an external source of amyloid pathology, then, on the one hand, it would explain the failure of traditional approaches to the treatment of Alzheimer's disease, and on the other hand, it would help to catch and nip it in the bud.
These guesses are based on examples of other neurodegenerative pathologies that come to the brain from the outside. This happens with prion proteins, which, like beta-amyloid (more precisely, this amyloid demonstrates prion-like behavior), form "snowballs" in the brain. Pathological forms of prion proteins enter the brain through the intestines: for example, Creutzfeld-Jakob disease can be picked up through cow meat, and Kuru disease – through ritual cannibalism. In rare cases, infection occurs through the blood – for example, if a person is injected with a drug obtained from the brain of a sick animal or another person (for Alzheimer's disease, by the way, such cases are also known, see Z. Jaunmuktane et al., 2015. Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy).
Similar mechanisms were found in a close "relative" of Alzheimer's disease – Parkinson's disease. The protein that causes it (and also behaves like a prion), alpha–synuclein, is considered to be the culprit for the fact that patients have impaired bowel function. And in experiments on mice, alpha-synuclein strands, which were injected into the intestinal muscles of animals, turned out to be in the brain after a month (see S. Kim et al., 2019. Transneuronal propagation of pathologic α-synuclein from the gut to the brain models parkinson’s disease). Therefore, a group of researchers from Hong Kong set out to find out whether beta-amyloid migration from the intestine to the brain is also possible.
To do this, they injected beta-amyloid labeled with fluorescent molecules into the mucous membrane of the stomach and various parts of the intestines of young mice. This made it possible to track the spread of injected beta-amyloid molecules through the body of mice in vivo literally live. It turned out that three hours after the injection, beta-amyloid began to penetrate into the submucosa, in which the muscles and processes of neurons innervating the intestine are located (Fig. 3).
Fig. 3. Intestines of mice three hours after administration of beta-amyloid molecules labeled with fluorescent dyes. Beta-amyloid glows red, the nuclei of cells are colored blue. A is a section of the intestine, yellow arrows indicate the direction of amyloid migration. B, C – amyloid spreads along the submucosa of the intestinal wall. An image from a discussed article in The Journal of Physiology.
On the third day, the labeled molecules could still be seen only around the injection, after a week the area with them began to slowly spread, and by the end of the first month it had captured the stomach and jejunum entirely (Fig. 4).
Fig. 4. The journey of fluorescent beta-amyloid through the mouse intestine. The red color corresponds to the maximum intensity of the glow of the labeled beta-amyloid molecules. A and B – state three hours after injection, C – three days later, D – a week later, E and F – a month later. An image from a discussed article in The Journal of Physiology.
A year after the start of the experiment, beta-amyloid reached the brain – plaques were found in the fibers of the vagus nerve, as well as in the hippocampus, amygdala and cerebral cortex. Amyloid aggregates were also found around the vessels of the brain. This symptom is known as cerebral angiopathy, and it occurs in most patients with Alzheimer's disease, although it does not serve as a diagnostic criterion (Fig. 5).
Fig. 5. Cerebral angiopathy in the human brain. Amyloid plaques are shown in brown. Drawing from the website en.wikipedia.org .
A year later, the authors of the work found other symptoms of pathology in mice. They gained weight (they became on average 4.6 g heavier than their relatives from the control group) and began to eat 20% more. But the same amount of waste was produced, from which the researchers first concluded that the mice had impaired intestinal function. Nevertheless, the intestines of the mice turned out to be all right, except for slow contractions of the jejunum. But this is understandable: in Alzheimer's disease, unlike Parkinson's disease, intestinal symptoms occur infrequently.
But the animals had deviations in cognitive functions. For example, when they were asked to memorize two objects, and then one of them was replaced with a new one, they did not pay more attention to it than to a familiar one. This, according to the authors, indicates problems with long-term memory.
The symptoms that the authors observed in mice do not fully reproduce human Alzheimer's disease. However, it should be borne in mind that mice do not suffer from it by themselves, and a pathology similar to it could only be caused in transgenic animals that produced an abnormally large amount of amyloid precursor protein APP. In the work under discussion, ordinary animals were used that are not prone to amyloid aggregation, so it is not surprising that their symptoms of the disease were only partially manifested. Nevertheless, the researchers were able to show for the first time that beta-amyloid, like prion proteins and alpha-synuclein, can enter the brain from the intestine.
After this work, at least two important questions remain open. Firstly, is such migration of beta-amyloid possible in humans and does it actually occur in patients with Alzheimer's disease? Or is it still a way that can be implemented theoretically, but does not occur in practice? Secondly, what kind of road does beta-amyloid use? The fact that it was found in the vagus nerve suggests that it can spread along sensitive fibers that go from the intestine to the brain. At least, this is how alpha-synuclein "moves", and its migration can be prevented if these fibers are cut. But it may also be that beta-amyloid migrates to the brain through the blood (it is known, for example, that macrophages are able to carry it into the brain, see A. F. Cintron et al., 2015. Transport of cargo from periphery to brain by circulating monocytes) – like, again, alpha-synuclein and prions. And if it turns out that there are different ways to spread from the intestine to the brain, this means that it will not be possible to do with a single biomarker for incipient Alzheimer's disease, and you will have to look for such markers in several places of the body at the same time.
Source: Sun et al., Intra‐gastrointestinal amyloid‐β1–42 oligomers perturbative enteric function and induce Alzheimer's disease pathology // The Journal of Physiology.
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