Malfunction in the right cells: scientists have found the early mechanism of Alzheimer's disease
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- Malfunction in the right cells: scientists have found the early mechanism of Alzheimer's disease
Alzheimer's disease can develop not only due to the accumulation of beta-amyloid, but also due to a molecular malfunction that disrupts the functioning of neural circuits at an early stage of the disease. Scientists from the Republic of Korea have discovered that the appearance of the ERBB4 receptor in excitatory neurons is accompanied by excessive activity of nerve cells, loss of synapses, an inflammatory reaction and memory impairment. In experiments on mice, disabling this mechanism weakened several signs of the disease at once. About how ERBB4 connects different pathological processes and whether the discovery can lead to the creation of a new treatment, see the Izvestia article.
Why amyloid plaques alone were not enough
Alzheimer's disease is usually associated with two of the most noticeable changes in the brain. Beta-amyloid protein accumulates between nerve cells, forming plaques, and pathological accumulations of tau protein occur inside neurons.
However, the development of the disease is not limited to this. Patients also gradually lose their synapses, the areas through which neurons transmit signals to each other. Nerve circuits become unstable, the cells of the brain's immune system become active, and chronic inflammation develops. Over time, a person experiences a deterioration in memory, thinking, and the ability to perform daily activities on their own.
The authors of the new study decided to find an early mechanism that could link neuronal hyperactivity, synapse loss, inflammatory response, and amyloid accumulation into a single pathological chain.
How synapse removal changes
The researchers paid special attention to astrocytes and microglia. These cells support the functioning of neurons, participate in the immune defense of the brain and remove unnecessary or damaged cellular structures.
In a healthy brain, such purification is necessary for the proper formation and restructuring of neural circuits. But with neurodegenerative diseases, it can be disrupted.
The researchers studied two mouse models of Alzheimer's disease, APP/PS1 and 5×FAD. It turned out that astrocytes and microglia did not just begin to actively absorb all synapses in a row. They selectively removed more excitatory contacts and at the same time fewer inhibitory ones.
Excitatory neurons enhance signal transmission, while inhibitory ones restrain excessive activity. A balance between them is necessary for the normal functioning of memory, learning and information processing. Its violation can simultaneously cause hyperactivity of some cells and weakening of other nerve circuits.
Changes in astrocytes appeared earlier than a similar reaction of microglia. In the APP/PS1 model, they became noticeable by about six months of the animals' life. In the 5×FAD model, disorders were detected as early as three months of age, when amyloid plaques began to form in the hippocampus.
At the same time, astrocytes absorbed more synapses than microglia, regardless of the animals' age, gender, and the disease model used.
The receptor appeared in the wrong cells
To identify the source of the disorders, the researchers analyzed the activity of genes in individual brain cells. They found a small group of excitatory neurons that began to change earlier than most of the surrounding cells.
The authors named them excitatory early response neurons — EREN. One of the main features of these cells was the abnormal appearance of the ERBB4 receptor.
ERBB4 belongs to receptor tyrosine kinases, proteins that receive external signals and transmit them inside the cell. In the central nervous system, this receptor is usually characteristic mainly of inhibitory neurons, including cells containing the protein parvalbumin. There, it participates in the development of synapses and the regulation of the activity of neural networks.
An experiment with the introduction of beta-amyloid oligomers showed that the amount of ERBB4 in CA1 excitatory neurons began to increase after two days. This indicates that amyloid may be one of the signals triggering the appearance of the receptor in these cells.
At the same time, EREN formation persisted in mice with impaired Trem2 gene function, which is associated with the transition of microglia to a state characteristic of Alzheimer's disease. Therefore, the change in excitatory neurons can begin at least partially independently of the immune response of microglia.
What happened after removing Erbb4
To test the role of the receptor, the scientists selectively disabled the Erbb4 gene in excitatory neurons of the CA1 region in mice with a model of Alzheimer's disease. At the same time, its work in inhibitory neurons has been preserved.
After the intervention, the excessive activity of excitatory neurons decreased. At the same time, the work of inhibitory cells containing somatostatin, which had previously been insufficiently active, was restored.
The process of synapse removal has also changed. Astrocytes and microglia began to absorb fewer excitatory and more inhibitory contacts, which brought their ratio closer to that of healthy animals.
The signs of the reactive state of astrocytes and microglia also decreased. The content of markers GFAP, S100b, and IBA1, which are used to assess glial response, decreased in brain tissues. There are fewer microglial cells carrying the AXL receptor and associated with pathological changes in neurodegeneration.
At the same time, the area and number of amyloid plaques in the hippocampus decreased. The mice improved on several tests of memory, object recognition, and spatial orientation, including the Barnes maze.
The effect persisted for a long time. Disabling Erbb4 at three months of age continued to affect the condition of the animals four months later. The intervention proved to be effective at a later stage: the introduction of a genetic construct into eight-month-old mice reduced the severity of pathology by the tenth month of life.
It is important that the researchers did not create a drug. For the experiment, viral vectors and a gene editing system aimed at a specific area of the brain and a specific type of neurons were used.
Why was there not enough suppression of activity
Scientists have separately tested whether it is possible to obtain the same result by simply reducing the activity of excitatory neurons. Short-term suppression of these cells really helped to normalize the absorption of synapses. However, it did not lead to a noticeable decrease in amyloid plaques and the reactive state of glial cells.
This means that ERBB4 affects the development of pathology not only through neural hyperactivity. The receptor probably triggers additional molecular programs that alter the functioning of neurons and their surrounding cells.
After removal of Erbb4, the activity of a number of genes involved in the formation and processing of the amyloid precursor protein decreased. Among them were App, Psen1, Ncstn and Bace1. This effect may partially explain the decrease in beta-amyloid, but the exact mechanism has yet to be established.
The painful disorders appeared without plaques
To reverse-test, the researchers turned on ERBB4 in the excitatory pyramidal neurons of healthy young mice. The receptor appeared in only 5-15% of these cells, about the same proportion that was observed in animals with a model of Alzheimer's disease.
Despite the small number of altered neurons, the animals developed disorders resembling a disease. Excitatory cells became hyperactive, the activity of inhibitory neurons decreased, and the ratio of synapses changed. Astrocytes and microglia have become reactive. The animals performed worse on memory, object recognition, and spatial orientation tasks.
At the same time, they did not have amyloid plaques. The result shows that improper activation of ERBB4 by itself can trigger a significant part of the pathological program, at least in the brains of mice.
When the scientists used a modified version of ERBB4 without a functioning kinase domain, similar violations did not occur. Therefore, for the development of pathology, it was the signaling activity of the receptor that was necessary, and not only its presence on the cell surface.
What research on the human brain has shown
To verify the clinical significance of the results, the scientists examined postmortem human brain samples. In people with Alzheimer's disease, ERBB4 was more often found in excitatory neurons containing the SLC17A7 marker than in people without dementia.
In addition, the authors analyzed data from 446 participants in the Religious Orders Study and Rush Memory and Aging Project. In these studies, the volunteers underwent regular cognitive examinations, and after their death, scientists studied the state of brain tissue.
High levels of ERBB4 in certain groups of excitatory neurons were associated with more pronounced amyloid deposits and worse results on the MMSE cognitive function assessment scale. Statistical modeling has shown that the variant in which an increase in ERBB4 precedes the accumulation of amyloid, changes in tau protein, and a decrease in cognitive abilities is in good agreement with the data obtained. However, such an analysis cannot prove a causal relationship.
Experiments on mice allow you to control the work of a particular gene and observe the consequences. In human research, we are talking about postmortem samples and statistical relationships. Therefore, it cannot yet be argued that ERBB4 triggers Alzheimer's disease in humans in the same way as in the animal models used.
When can a new treatment be available?
The discovery makes ERBB4 a potential target for further therapy development. Its advantage lies in the fact that influencing this mechanism can theoretically weaken several interrelated processes at once: hyperactivity of neurons, loss of synapses, reaction of glial cells, accumulation of amyloid and cognitive impairment.
However, direct systemic blocking of the receptor may not be safe. ERBB4 performs normal functions in inhibitory neurons, so the future method should act primarily on those excitatory cells in which the receptor appeared as a result of the disease. The ability to provide such accuracy in humans has not yet been demonstrated.
Other issues remain. It is unknown which molecules activate ERBB4 at different stages of the disease, why the receptor is activated only in parts of neurons, and to what extent the mechanism is related to tau pathology. The mouse models used primarily reproduce the formation of beta-amyloid and do not reflect the full complexity of Alzheimer's disease in humans.
The authors also point to the need to test the role of EREN and ERBB4 in other forms of neurodegeneration. A preliminary analysis of the open data revealed similar cellular conditions in progressive supranuclear palsy and an association with the severity of Huntington's disease, but these observations require separate confirmation.
Thus, ERBB4 cannot be considered the sole cause of Alzheimer's disease, and treatment against it is not yet ready for trials on patients. Nevertheless, the study offers a possible explanation for how a small section of altered neurons is able to rearrange the work of surrounding cells and start a self-sustaining chain of damage.
Переведено сервисом «Яндекс Переводчик»
