Blocking an Astrocyte Receptor Produces Benefits in an Alzheimer's Mouse Model
Researchers here produce an interesting demonstration in a mouse model of Alzheimer's disease. With a comparatively simple change, they rein in the abnormal behavior of astrocyte cells in the brain, and thereby reverse the symptoms of the condition. As noted in the publicity materials, the relevance of mouse models of Alzheimer's to the real thing in humans is often strained - the models are highly artificial, as mice and most other mammals don't normally suffer anything resembling Alzheimer's disease. Thus in cases like this it is hard to say without further work whether or not the discovery is relevant to human biochemistry.
Nonetheless, the supporting cells of the brain, the various categories of neuroglia such as the astrocytes noted here, cannot be ignored in the progression neurodegenerative conditions. They perform a wide range of important functions: clearing up debris and waste; supplying necessary proteins and other molecules to neurons; participating in the maintenance and operation of synaptic connections between neurons; and much more. In neurodegenerative conditions such as Alzheimer's disease, the neuroglia malfunction or change their behavior in harmful ways. Chronic inflammation is one consequence, but also disruption of the normal function of neural networks.
In studies in mice, researchers were able to show that blocking a particular receptor located on astrocytes normalized brain function and improved memory performance. Astrocytes are star-shaped, non-neuronal cells involved in the regulation of brain activity and blood flow. "The brain contains different types of cells including neurons and astrocytes. Astrocytes support brain function and shape the communication between neurons, called synaptic transmission, by releasing a variety of messenger proteins. They also provide metabolic and structural support and contribute to the regulation of blood flow in the brain."
Similar to neurons, astrocytes are organized into functional networks that may involve thousands of cells. "For normal brain function, it is crucial that networks of brain cells coordinate their firing rates. Interestingly, one of the main jobs of astrocytes is very similar to this: to keep neurons healthy and to help maintain neuronal network function. However, in Alzheimer's disease, there is aberrant activity of these networks. Many cells are hyperactive, including neurons and astrocytes. Hence, understanding the role of astrocytes, and targeting such network dysfunctions, holds a strong potential for treating Alzheimer's."
Researchers tested this approach in an experimental study involving mice. Due to a genetic disposition, these rodents exhibited certain symptoms of Alzheimer's similar to those that manifest in humans with the disease. In the brain, this included pathological deposits of proteins known as amyloid-beta plaques and aberrant network activity. In addition, the mice showed impaired learning ability and memory. The scientists targeted a cell membrane receptor called P2Y1R, which is predominately expressed by astrocytes. Previous experiments had revealed that activation of this receptor triggers cellular hyperactivity in mouse models of Alzheimer's. Therefore, the researchers treated groups of mice with different P2Y1R antagonists. These chemical compounds can bind to the receptor, thus switching it off. The treatment lasted for several weeks.
"We found that long-term treatment with these drugs normalized the brain's network activity. Furthermore, the mice's learning ability and memory greatly improved. On the other hand, in a control group of wild type mice this treatment had no significant effect on astrocyte activity. This indicates that P2Y1R inhibition acts quite specifically. It does not dampen network activity when pathological hyperactivity is absent. This is an experimental study that is currently not directly applicable to human patients. However, our results suggest that astrocytes, as important safeguards of neuronal health and normal network function, may hold the potential for novel treatment options in Alzheimer's disease."
This result shows that the mouse model is rather a autoimmune reaction where astrocytes damage neurons for some reason. A similar effect might be a contributing factor to humans. But unlikely a major one.