A novel system for drug discovery
The pharmaceutical industry mainly uses cellular assays to assess drug effectiveness, yet this doesn’t provide information about the effects on neuronal communication, which is disrupted in neurodegenerative diseases. Researchers in the NEUREKA project are developing a novel drug screening system which could facilitate the drug discovery process for neurodegenerative diseases, as Dr Yiota Poirazi explains.
The majority of systems currently used to screen drugs against Alzheimer’s disease involve the use of neurons from patients or animal models in cellular assays. However, these systems don’t fully reflect the conditions in which the disease develops and progresses, as they capture mostly the molecular but not the electrophysiological phenotype of the disease. As the Principal Investigator of the EU-funded NEUREKA project, Dr Yiota Poirazi is working to develop a new system to model neurodegenerative diseases like Alzheimer’s, which could prove to be an invaluable tool in drug development. “We believe that if we can develop a more realistic representation of brain diseases, whereby both the physiological and molecular characteristics are captured, then it’s more likely to help in finding effective drugs,” she outlines. A lot of the drugs developed to treat Alzheimer’s fail during the regulatory process; the lack of a realistic environment for screening them has been identified as one potential factor in this, something that Dr Poirazi and her colleagues are working to address. “The NEUREKA project aims to change the drug screening process by introducing a hybrid system whereby cultured
neurons are driven by computational models of Alzheimer’s, so as to replicate the disease pathophysiology in vitro,” she says.
Alzheimer’s disease
In Alzheimer’s, calcium ions get into neurons - the main cells in the brain responsible for processing information - which causes neurotoxicity and eventually leads to cell death. “Dendrites, which are essentially the receiving ends of neurons, start to shrink and connections between neurons are lost. There is degradation of neurons in the brain, and eventually neuronal death, because of this toxicity and shrinkage. This neuronal loss leads to deficits in behaviour, memory loss and confusion,” explains Dr Poirazi.
In the project, Dr Poirazi is developing a computational circuit model of neurons, whose morphology and electrical properties are based on experimental data. “It’s a constrained, realistic, computer-based model consisting of a few hundred neurons,” she explains. “In terms of its biophysical properties, like its excitability or its synaptic properties, it is designed to reproduce what is seen in Alzheimer’s neurons.”
The computational model is then used to drive activity in cultured neurons, derived from human induced pluripotent stem cells (iPSC). Researchers are essentially recreating human neurons in cultures on a chip; initially these neurons are in a healthy state, but then they are exposed to certain chemical agents, leading to the development of the disease.
“The cultured neurons produce these amyloid beta proteins that accumulate in dendrites of Alzheimer’s patients. We start seeing synaptic deficits and dendritic atrophy, and slowly we are able to reproduce the disease in vitro We will be reproducing it in a continuous manner, starting from the early phases, all the way through to the more severe, advanced stages,” outlines Dr Poirazi. The focus is on neurons
in those areas of the brain related to the human physiology of the disease, primarily the hippocampal neurons. “The hippocampus is the site with the most severe deficits in Alzheimer’s,” says Dr Poirazi. “We will also be using some cortical neurons, as the entorhinal cortex is where the disease is initiated.”
A novel Nanowire Chip
Cultured neurons are connected with the computational network model via nanowire electrodes that allow direct access to subcellular compartments of neurons, like their dendrites. Dr Poirazi says it’s possible to drive learning and memory activity in both the biological and simulated networks through this integrated system. Information can be presented to the computational network, which has various plasticity mechanisms, and it can learn to encode it. “By learning we mean that you can present just a piece of the original information, and the network responds as if you have presented the entire thing. So it completes the missing information. This is how learning is simulated in a network,” explains Dr Poirazi. The same approach can be taken with the cultured neurons, as they are inter-connected with the computational network. “When a memory is presented to the network it drives a particular activity, which is also then delivered to the cultured neurons,” continues Dr Poirazi. “This should drive changes in the cultured
are effective in inducing plasticity changes in these networks. We can also put drugs that help in inducing these changes, and try to achieve a reversal of the Alzheimer’s phenotype,” she outlines. “If a drug is able to reverse these deficits, we will be able to see that when we train the system so as to learn new information.”
Smart, multi-scale drug discovery
The NEUREKA project introduces a smart, multi-scale drug discovery system that Dr Poirazi says is very different from the cellular assays commonly used in the pharmaceutical industry. While conventional cellular assays enable researchers to see whether a drug leads to improvements at the molecular level, the NEUREKA system provides a significantly higher level of detail. “Our system provides information about deficits and restoration at the dendritic and the neuronal circuit levels.
It’s a multi-scale system, as we can still zoom in and look at molecular changes,” explains Dr Poirazi. This system could be used not only in assessing the effectiveness of drugs, but also in guiding future development. “It could be used effectively as a prediction system for finding new drug targets,” says Dr Poirazi. “We can look at different properties – subcellular, cellular and circuit level effects of the disease – and then design drugs that target those different properties.”
NEUREKA
A hybrid neural-silico-computo device for drug discovery
Project Objectives
Researchers in the NEUREKA project are working to develop an innovative hybrid technology, combining nanoelectrodes and sophisticated computational models of neuronal circuits. This enables researchers to readout and manipulate activity/ connectivity in cultured neuronal networks of Alzheimer’s disease at subcellular accuracy, opening up new insights into the disease.
Project Funding
Alzheimer Europe’s database on research projects was developed as part of the 2020 Work Plan which received funding under an operating grant from the European Union’s Health Programme (2014–2020).
Grant agreement ID: 863245.
Project Partners
• Universita Degli Studi Di Padova
• Universita’ Degli Studi Di Milano-Bicocca
• Maxwell Biosystems Ag
• Centre National De La Recherche Scientifique Cnrs
• Idryma Technologias Kai Erevnas
Contact Details
Dr Yiota Poirazi, PhD
Group Leader / Director of Research, Institute of Molecular Biology and Biotechnology (IMBB) Foundation for Research and TechnologyHellas (FORTH)
Heraklion
Greece
T: +302810 391139
E: poirazi@imbb.forth.gr
W: http://neureka.gr
W: https://dendrites.gr
neurons as well, so when the network learns something, the cultured neurons should also be able to learn it. The activity in the cultured neurons is fed back to the computational model, in a closed-loop manner, thus allowing the biological and computational networks to learn in synchrony.”
Recent studies have shown that cultured neurons can learn to deal with simple problems, for example playing the video game Pong, now researchers in the project are using cultured neurons in a similar way. The idea here is to probe deeper into the impact of Alzheimer’s disease and assess the learning capacity of the cultured neurons. “In Alzheimer’s, memory is greatly impaired. We want to see what properties these cultured neurons lack. Can they still learn and pick up new information? To what extent can they do so?” says Dr Poirazi. Once the neurons have been characterised, Dr Poirazi aims to try and reverse any deficits. “This could involve delivering particular stimuli that we know
The primary focus in the project is Alzheimer’s disease, yet Dr Poirazi is clear that the framework holds wider potential and could also be applied to other neurodegenerative diseases. This would require a new computational model specific to the particular disease, as it is the model which essentially drives changes in the cultured neurons, an avenue which Dr Poirazi could explore in future. “If there is industrial interest in this research then we could look into extending the technology to other neurodegenerative diseases,” she outlines. The project is still in its early stages however and there aren’t any clear exploitation plans as of yet, with the current priority more to demonstrate that the system as a whole works efficiently. “The goal is to demonstrate the feasibility of this technology as a proof-of-concept, which we hope will happen in the next few months,” continues Dr Poirazi. “We are not aiming to find new drugs, but to offer a technology that can be used for drug screening.”
Dr Yiota Poirazi is a Research Director at IMBB-FORTH, where she leads a laboratory investigating dendrites. The main focus of the group’s research is how the integrative properties of dendrites contribute to learning and memory functions.
We believe that if we can develop a more realistic representation of brain diseases then it’s more likely to help in finding good, effective drugs.Dr Yiota Poirazi, PhD CNRS-LAAS Clean Room. Figure showing the components of the NEUREKA project.