Blocking the P2Y1 receptor on astrocytes normalized brain function and improved memory performance in studies with mice, a study by scientists of the German Center for Neurodegenerative Diseases (DZNE) reports.
The finding points to a potential approach against Alzheimer’s disease.
Alzheimer’s disease is an incurable brain disorder leading to dementia. its mechanisms remain incompletely understood. The disease appears to be sustained by a combination of factors that include pathological changes in blood flow, neuroinflammation and detrimental changes in brain cell activity.
“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,"
explained first author Dr. Nicole Reichenbach, a postdoc researcher at the DZNE.
Network Activity Glitch
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. It’s like in a symphony orchestra where the instruments have to be correctly tuned and the musicians have to stay in synchrony in order to play the right melody.
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 in 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,"
said Professor Gabor Petzold, a research group leader at the DZNE and supervisor of the current study.
Petzold and colleagues 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.
In their study, the researchers targeted a cell membrane receptor called P2Y1R, which is predominately expressed by astrocytes. Previous experiments by Petzold and colleagues 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,"
Petzold said. 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."
In future studies, the scientists intend to identify additional novel pathways in astrocytes and other cells as potential drug targets.
Nicole Reichenbach, View ORCID ProfileAndrea Delekate, Björn Breithausen, Kevin Keppler, Stefanie Poll, Theresa Schulte, Jan Peter, Monika Plescher, View ORCID ProfileJan N. Hansen, Nelli Blank, Armin Keller, Martin Fuhrmann, Christian Henneberger, Annett Halle, View ORCID ProfileGabor C. Petzold P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer’s disease model Journal of Experimental Medicine May 2018, jem.20171487; DOI: 10.1084/jem.20171487
Image: Star-shaped astrocytes (green) gathered around pathological protein deposits (purple). These “plaques” are a hallmark of Alzheimer’s disease. Credit: DZNE / Nicole Reichenbach