In terms of the treatment of Alzheimer's disease, the US Food and Drug Administration has only approved one amyloid antibody drug for the treatment of the disease, and on the other hand, the cause, pathogenesis and treatment of Alzheimer's disease are still important issues of concern to scientists.
The study published in Neuron also focused on this issue, discovering a completely new mechanism of Alzheimer's disease and pointing the way to potential treatments for the disease. So what exactly is this new mechanic? We should have a new understanding of Alzheimer's disease.
First, what is Alzheimer's disease? "Science" sub-issue: It turns out that the memory is "hungry"
Many people's understanding of Alzheimer's disease is limited to the fact that it is a neurodegenerative disease that affects brain memory and cognitive ability, and can have extremely inconvenient effects on the health and life of the elderly. Research in the Science sub-journal showed that Alzheimer's disease is related to memory loss, cognitive impairment and resistance to "ghrelin".
The researchers analyzed brain tissue samples from Alzheimer's disease patients after death and found that β amyloid binds to the ghrein receptors of the hippocampus, and when the ghregin receptors are "controlled" by β amyloid, it cannot rebind to dopamine receptors, which will cause synapses between nerves to be lost, thereby damaging memory.
Do you feel that this mechanism is familiar?
Due to insulin resistance, under the influence of the compensatory effect, the body of early type II diabetes patients will produce more insulin to bind to insulin receptors, but no matter how much insulin the body produces, it is difficult for insulin receptors to activate downstream biochemical reactions and send glucose in the blood into cells, so that the similar mechanism is what we know as diabetes.
In the brain of Alzheimer's patients, amyloid binds to ghrelin receptors β, and even if the body increases how much ghrelin and increases the amount of GHSR1α in the brain, these receptors cannot function. In this way, the researchers found that Alzheimer's disease may be related to ghrelin resistance.
But what is ghrelin? What is the relationship between it and Alzheimer's disease?
It sounds like ghrelin is related to hunger, but it does promote appetite. To be precise, ghrelin is a hormone produced in the stomach that can signal to the brain to regulate weight and energy balance, but what we are talking about here is the role of ghrelin related to learning and memory.
There is a brain area in our brain that is important for memory, mood and learning, and it is also one of the first areas attacked by Alzheimer's disease, the hippocampus. In general, in a healthy hippocampus, ghrelin binds to the receptor GHSR1α, and the receptor also combines with the dopamine-activating receptor to form a protein complex designed to facilitate communication between brain cells and maintain memory.
When toxic proteins in amyloid β accumulate in the hippocampus, it leads to nerve cell death, which is one of the early symptoms of Alzheimer's disease. Then the researchers conducted a clinical experiment: using specific compounds to try to activate GHSR1α in the brain to see if it could slow the progression of Alzheimer's disease.
The result shows that the answer is no. At this time, the researchers made a bold hypothesis that the separation of ghregin receptors and dopamine receptors may be an important reason for the cognition of Alzheimer's patients: when ghrelin receptors are protected, enhancing dopamine receptors at the same time may promote the formation of complexes between the two receptors.
The results of subsequent experiments showed that this hypothesis was valid. When both drugs were injected at the same time, the memory and cognitive abilities of Alzheimer's mice improved, and the connections between nerve cells in the hippocampus were enhanced, and lesions were reduced. This means that activating both receptors at the same time is the key point. So when talking about the mechanism of Alzheimer's disease, we may really be able to say that the memory is "hungry".
Second, the "Neuron" research found a new mechanism, pointing the way for potential therapies for Alzheimer's disease
As a neurodegenerative disease, there is no cure for Alzheimer's disease, and many pharmaceutical companies at home and abroad have spent countless efforts to develop new drugs for Alzheimer's disease, and almost nothing has changed.
In the face of the high number of patients and the heavier burden of the disease, many scientists are working hard to overcome new ways and treatments for Alzheimer's disease, and the research published by Chinese researchers in "Neuron" has also paid attention to this problem, and the results it brings point the way for potential treatment of Alzheimer's disease.
The researchers found that the lethal risk posed by the ApoE isomer is related to the direct and specific inhibition of the Y-shear activity of amyloid precursor proteins, and proposed a new theory that the ApoE isomer changes Alzheimer's disease, that is, because ApoE2 has the strongest inhibitory activity and ApoE4 loses this activity, it will lead to completely different pathogenic consequences for the two.
Before clarifying the above conclusions, we need to understand that one of the pathological features in the brains of Alzheimer's disease patients is the presence of a large number of amyloid plaques, but the relationship between them and memory and cognitive decline is still controversial. For example, most of the current understanding of the fatal mechanism of Alzheimer's disease comes from the study of family inheritance, that is, the excessive aggregation of amyloid will accelerate the occurrence of Alzheimer's disease.
This may be because amyloid precursor proteins will be continuously cleaved under the influence of special enzymes and produce peptides, the key Y secretase enzyme cleavage activity center, some mutations will accelerate the formation of amyloid plaques, leading to the emergence of familial inherited Alzheimer's disease.
The study published by the Interdisciplinary Research Center of Biology and Chemistry of the Chinese Academy of Sciences is the first to directly link the risk genes of familial hereditary Alzheimer's disease and non-familial sporadic Alzheimer's disease functionally, suggesting that abnormal Y digestion of amyloid precursor protein is the common cause of the two diseases.
Although the treatment of sporadic Alzheimer's disease based on the removal of amyloid plaques has been clinically verified, this type of therapy can only partially reduce the exacerbation of Alzheimer's disease, and the treatment effect is limited.
It is worth noting that this study also found that the ApoE active region can accurately locate amyloid around amyloid plaques, neuronal high incidence areas, and inhibit the production of amyloid protein in brain cells from the source in a highly specific way, thereby reducing amyloid plaques, which may point out a new direction for potential Alzheimer's disease therapies.
Don't look too small to be inconspicuous, but it may help ward off Alzheimer's disease
Dutch researchers have discovered a tiny RNA molecule that can play an important role in cell function in the brain, which is expected to become a therapeutic target for Alzheimer's disease in the future.
But what are tiny RNA molecules?
In simple terms, RNA can help produce proteins, in addition to RNA involved in translation and transcription, including RNA fragments that are not involved in protein coding, including microRNAs. It can be said that the role of microRNA molecules and its size really do not match, because from the current point of view, many microRNAs have been found to regulate gene expression, which in turn affects the level of proteins, and those abnormal microRNA levels may promote the development of diseases.
In the case of the microRNA-132 molecule, it is one of the most strongly downregulated microRNA molecules in the brains of Alzheimer's patients, and it is also an inhibitory neuronal regulator. Previous studies have shown that increasing the microRNA molecules in the brains of mice with Alzheimer's disease can improve Tau pathology, amyloid, etc., and can also cause hippocampal neurogenesis and memory deficits.
However, the functional pleiotropism of microRNAs needs to be deeply analyzed and the effect of supplementing microRNAs can be used to treat Alzheimer's disease. The study, published in the journal Cell, found that the microRNA expression profile of Alzheimer's patients is often confused, especially the microRNA-132 is significantly reduced.
In fact, previous studies have shown that re-upgrading microRNA-132 levels can improve memory in Alzheimer's disease model mice and promote brain cell regeneration, so the researchers of the paper believe that these missing microRNAs are not a coincidence.
In order to further clarify the specific role of microRNA-132, the researchers controlled the level of microRNA-132 in mice, collected different cell types in the brains of experimental mice, and finally sequenced the RNA.
The results showed that microRNA-132 did play an important role, especially when it was in microglia, the lower the level of microRNA-13, the higher the inflammation level of the corresponding microglia, and when the researchers re-raised the level of microRNA-132, the state of the cell slowly returned to normal inflammation levels. This may be because microglia are immune support cells in the brain that determine the level of inflammation in nerve tissue.
The researchers concluded that this abnormal state of cellular inflammation may lead to the death of surrounding healthy cells to promote the emergence of Alzheimer's disease.
Bibliography:
【1】Xianglong Hou, Xuexin Zhang.Differential and substrate-specific inhibition of γ-secretase by the C-terminal region of ApoE2, ApoE3, and ApoE4.2023.04.10.
【2】Hannah Walgrave, Amber Penning.microRNA-132 regulates gene expression programs involved in microglial homeostasis.2023.05.05.
【3】Jing Tian, Lan Guo.Disrupted hippocampal growth hormone secretagogue receptor 1α interaction with dopamine receptor D1 plays a role in Alzheimer′s disease.2019.08.14.