Alzheimer’s numbers are reaching record highs, but there is still no drug that can cure or stop Alzheimer’s disease. Even the latest drug developments for Alzheimer’s can, at best, relieve the symptoms. Nevertheless, mental deterioration continues, with sometimes fatal side effects and enormous therapy costs.
It is now well known that in this dreaded disease, neurons (nerve cells) in the brain, especially in the region of the hippocampus (site of episodic memory) die. That’s why a report in the press has made people sit up and take notice: Researchers from Belgium have investigated the cause of this cell death in more detail and have tracked down the underlying mechanisms.
A novel Alzheimer’s animal model
One animal model frequently used in Alzheimer’s research is mice that have had the gene defect responsible for familial Alzheimer’s disease “inserted” into them. These animals develop the Alzheimer’s-specific deposits (Aβ-plaques) quite soon. However, not all stages of the disease process take place in the neurons of these mice. This includes the formation of neuronal tangles from tau protein as well as extreme neuronal cell death. For this reason, this animal model has been of limited use in Alzheimer’s disease research.
A Belgian research team has further developed this Alzheimer’s animal model . The scientists implanted human neural stem cells (precursors of human nerve cells) into the brains of Alzheimer’s mice. The human neurons differentiated and fully integrated into the animal brain, dhe human nerve cells worked normally in the nervous system of the mice from this point on. With onset of the disease, after a short time they were already exposed to Aβ deposits (produced by the mouse neurons) and the associated brain inflammation (neuroinflammation). exposed. As a result, the harmful tau clusters formed six months later. Interestingly, this happened only in the human neurons that were inserted into the mouse brain. According to the authors, this suggests that Aβ stimulates tau aggregation early and that this process is a human characteristic. The formation of tau fibrils also eventually led to the death of human neurons.
In this chimeric (consisting of cells/tissues of different individuals) animal model, the human neurons in the brains of the mice thus developed the full spectrum of Alzheimer’s disease. This is because they showed damaging tau fibrils and high levels of neurodegeneration in addition to Aβ-plaques and neuroinflammation. This novel Alzheimer’s animal model is predestined for mechanistic studies because of these features. The research group now looked into the question of how neurons die in Alzheimer’s disease. The results of these studies were recently published in the renowned journal Science published.
The molecule MEG3 drives cell death, the necroptosis
Also in these studies, only the human neurons in the chimeric Alzheimer’s mice showed disease markers such as tau tangles, and they died at an increased rate. Using RNA sequencing (determination of RNA building blocks), the scientists were able to identify the key molecule, an RNA structure called MEG3(Maternally Expressed 3) to identify. Molecules of this kind are recognised for regulating gene activity, which affects brain ageing and therefore neurodegenerative diseases. MEG3 was increased tenfold in human “diseased” neurons in mouse brains and was also found in large amounts in neurons of deceased Alzheimer’s patients. Also, when this molecule is added to “live” human brain cells in the test tube, these cells die. MEG3 thus appears to be the trigger for a form of programmed cell death (necroptosis) that leads to the death of human neurons .
MEG3 blockers as a new drug class?
Such studies are important to understand precisely the mechanisms underlying this neuronal death. The authors conclude that MEG3 could become an important target for future research and therapies aimed at preventing neuronal death in patients with Alzheimer’s disease.They think that based on these data, a new type of Alzheimer’s drug could be developed: MEG3 blockers.
But until then, a lot of research is still needed: the findings from the animal model cannot be directly transferred to the complete human organism. Moreover, from the mouse model induced familial Alzheimer’s disease cannot be directly inferred from sporadic (or late) Alzheimer’s disease.. The latter form represents the most common form of Alzheimer’s disease, accounting for about 99% of all cases (more info can be found here).
Whether MEG3 blockers will be the future miracle pill against Alzheimer’s, or rather just another ineffective symptomatic therapy like the antibody drugs, therefore, remains to be seen.
What is already known with certainty, however, is that the first molecular changes in the brain in Alzheimer’s disease occur long before the onset of clinical symptoms. The most effective strategy in the fight against this devastating disease is early prevention through a healthy lifestyle.
You are welcome to read beat the “Knowledge stops Dementia“,how you can take your mental health into your own hands through simple measures such as diet optimization, more exercise, improved sleep, compensation of micronutrient deficiencies, more social activity, brain training and improved stress management!
Alzheimer’s disease remains a mystery to the scientific community, but a recent study published in the prestigious journalSciencesheds new light on the underlying mechanisms of this devastating disease.
Using a novel chimeric Alzheimer’s mouse model to study the full spectrum of Alzheimer’s disease, we identified the molecule MEG3, which causes a type of cell death in human neurons called “Necroptosis” is able to trigger. The authors conclude that necroptosis follows the accumulation of pathological tau protein and is triggered by accumulation of MEG3 and that it may be a therapeutic target in the future. However, many more studies are needed before then.
Until then, you can learn how to take control of your mental health right now through simple lifestyle-oriented measures at Knowledge Stops Dementia!
- Espuny-Camacho, I., Arranz, A. M., Fiers, M., Snellinx, A., Ando, K., Munck, S., Bonnefont, J., Lambot, L., Corthout, N., Omodho, L., Eynden, E. V., Radaelli, E., Tesseur, I., Wray, S., Ebneth, A., Hardy, J., Leroy, K., Brion, J.-P., Vanderhaeghen, P., & Strooper, B. D. (2017). Hallmarks of Alzheimer’s Disease in Stem-Cell-Derived Human Neurons Transplanted into Mouse Brain. Neuron, 93(5), 1066-1081.e8. https://doi.org/10.1016/j.neuron.2017.02.001
- Balusu, S., Horré, K., Thrupp, N., Craessaerts, K., Snellinx, A., Serneels, L., T’Syen, D., Chrysidou, I., Arranz, A. M., Sierksma, A., Simrén, J., Karikari, T. K., Zetterberg, H., Chen, W.-T., Thal, D. R., Salta, E., Fiers, M., & De Strooper, B. (2023). MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer’s disease. Science, 381(6663), 1176-1182. https://doi.org/10.1126/science.abp9556
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