Alzheimer’s is the sixth leading cause of death for all ages and the fifth leading cause of death for those 65 years of age and older, with an annual cost of approximately $226 billion in the U.S. alone. But its treatment remains with symptom-preventing drugs that neglect the diseases progression or do not cure the disease. Alzheimer’s main cause is the lack of glutamate in the tripartite synapses (three way molecular communication between neurons and astrocytes), which leads to poor synaptic transmission and therefore lack of memory, bad sleep, depression, etc. The control of the concentration of glutamate can, therefore, increase the synaptic quality, providing a new and potentially more efficient way to treat Alzheimer’s. Since glutamate release is controlled by the intracellular Ca2+ signalling in the astrocytes of the tripartite synapses, providing desired levels of Ca2+ ions can result in the desired regulation of glutamate.
The IRC post-doc from TSSG, Dr. Michael Taynnan Barros, together with a Professor from the University of South Australia (and now in Maynooth Univerisy), Dr. Subhrakanti Dey, proposed the use of feed-forward feedback control theory, combined with communication theory and synthetic biology, to regulate the internal Ca2+ signalling of astrocytes in the tripartite synapses, providing sufficient levels of glutamate to control the quality of the synaptic transmission. In Fig. 1, one can see that this mechanism can control the intracellular Ca2+ signalling using analogies from digitalization of Ca2+ oscillations, where the effects of the refractory periods are the leading cause of noise or inter-symbol interference.
Figure 1. The tripartite synapes, the feed-forward feedback control solution, and the digitalization of ca2+ oscilations
The major contributions from this work are the 1) Regulation of Ca2+ Signalling in Astrocytes: A mathematical framework is developed to calculate the desired Ca2+ levels based on a given desired IP3 value and also the stability of the system (the system in this context is the point of communication between the astrocyte and neuron inter-cellular signalling). Finally, a disturbance analysis is used to investigate the benefits of having a feed-forward component in the control design. The proposed technique achieves the control of Ca2+ levels in the cytosol of astrocytes with proven stability. 2) Improved Performance of Molecular Communication System: The use of Ca2+ signalling for molecular communication can result in a high quantity of noise propagating through the tissue, resulting in low data rates. However, the control theoretic method proposed in this work regulates the Ca2+ levels, resulting in a minimum amount of noise, which in turn achieves superior communication performance with increased data rate, improving the gain and decreased delay. As depicted in the bottom of Fig. 1, the digitalization of the calcium pulse is the main driver of the increased performance, by eliminating the refractory period and decreasing noise in the channel.
With an increased level of control, the researchers show how they achieved regulated oscillatory control of intracellular Ca2+ concentration, as illustrated in Fig. 2. Compared to the pre-synaptic influence, with a 4Hz firing of the presynaptic neuron, regulated oscillatory control can be achieved by the continuous calcium regulation. Even though the results are satisfactory, this type of control is consequently harder to implement in experimental settings due to the oscillatory behaviour that the control has to have. This requires a more complex implementation systems that use cellular reprogramming techniques from synthetic biology, which can integrate monitoring and stimulation of a cell to the oscillatory regulation function.
Figure 2 Regulated oscillatory control of Ca2+ oscillation using the proposed feedback and feed-forward control technique. Irregular Ca2+ oscillations from pre-synaptic influence C (dashed line) is compared to a controlled Ca2+ level C ∗ (solid line) for IP3 = 0.5 (µM).
The proposed approach can potentially lead to novel nanomedicine solutions for the treatment of neurodegenerative diseases, where a combination of nanotechnology and gene therapy approaches can be used to elicit the regulated Ca2+ signalling in astrocytes, ultimately improving neuronal activity. This is not only applicable to Alzheimer’s but also to other neurodegenerative diseases. This ongoing research work will cause a significant impact in biotechnology, nanotechnology, and drug delivery systems. This work was funded by the Irish Research Council under the grant GOIPD/2016/650.