Periodic Reporting for period 4 - SweetBrain (A new perspective on the metabolic pathway to neuronal dysfunction: Using organs on a chip to elucidate the role of the brain microvasculature)
Okres sprawozdawczy: 2025-03-01 do 2025-11-30
Diseases of the central nervous system, including Alzheimer’s disease and other neurodegenerative disorders, represent one of the greatest medical and socioeconomic challenges of modern society. At the same time, the prevalence of metabolic disorders such as diabetes and chronic hyperglycemia has increased dramatically worldwide. Epidemiological evidence links elevated blood glucose levels with increased risk of neurodegeneration, yet the mechanistic pathway connecting high sugar levels to neuronal dysfunction remains largely unresolved.
Traditionally, research has focused on direct interactions between neurons and astrocytes. This project addressed a critical gap: the role of the brain microvasculature—the blood-brain barrier (BBB) and broader neurovascular unit (NVU)—as an active mediator between systemic metabolic changes and neuronal health. Because circulating metabolites must pass through the vasculature before reaching neurons, we hypothesized that the vasculature is not merely a passive barrier, but a dynamic metabolic interface that may drive or modulate neurodegenerative processes under hyperglycemic conditions.
This question is societally important. Modern societies are characterized by high sugar consumption and rising rates of obesity and diabetes. Understanding how elevated glucose levels affect brain function is essential for reducing long-term neurological consequences of metabolic disease and may open new avenues for prevention and therapy.
To address this challenge, we developed advanced human-relevant Organs-on-a-Chip (OoC) technologies to model the NVU in a controlled and physiologically relevant manner. These platforms allowed us to decouple, yet metabolically and functionally couple, vascular and neuronal compartments, enabling mechanistic investigation of cell–cell interactions not accessible in conventional models.
The overall objectives were:
Aim 1. Establish a human-relevant NVU model for metabolic and functional interactions.
Aim 2. Identify major metabolic and functional interactions in the NVU at homeostasis and under diabetic conditions.
Aim 3. Target vasculature–neuron communication to diminish neuronal dysfunction.
This project contributed to a conceptual shift in understanding metabolic contributions to neurodegeneration. Rather than focusing exclusively on neuron–astrocyte interactions, our findings highlight the dynamic role of the vasculature in mediating metabolic effects on neuronal function.
Key outcomes include:
• Development of advanced NVU-on-a-chip technologies with integrated functional readouts.
• Demonstration that extreme hyperglycemia impairs BBB integrity and neuronal activity.
• Discovery that glucose effects are context-dependent, with moderate elevations potentially supporting recovery after injury.
• Establishment of a human-relevant platform for studying insulin signaling, metabolic stress, infection, trauma, and additional neurovascular pathologies.
Overall, this work advances a refined paradigm in which the NVU acts as a metabolic regulator translating systemic metabolic states into neuronal outcomes, opening new avenues for understanding and mitigating neurological consequences of metabolic disease.
Traditionally, research has focused on direct interactions between neurons and astrocytes. This project addressed a critical gap: the role of the brain microvasculature—the blood-brain barrier (BBB) and broader neurovascular unit (NVU)—as an active mediator between systemic metabolic changes and neuronal health. Because circulating metabolites must pass through the vasculature before reaching neurons, we hypothesized that the vasculature is not merely a passive barrier, but a dynamic metabolic interface that may drive or modulate neurodegenerative processes under hyperglycemic conditions.
This question is societally important. Modern societies are characterized by high sugar consumption and rising rates of obesity and diabetes. Understanding how elevated glucose levels affect brain function is essential for reducing long-term neurological consequences of metabolic disease and may open new avenues for prevention and therapy.
To address this challenge, we developed advanced human-relevant Organs-on-a-Chip (OoC) technologies to model the NVU in a controlled and physiologically relevant manner. These platforms allowed us to decouple, yet metabolically and functionally couple, vascular and neuronal compartments, enabling mechanistic investigation of cell–cell interactions not accessible in conventional models.
The overall objectives were:
Aim 1. Establish a human-relevant NVU model for metabolic and functional interactions.
Aim 2. Identify major metabolic and functional interactions in the NVU at homeostasis and under diabetic conditions.
Aim 3. Target vasculature–neuron communication to diminish neuronal dysfunction.
This project contributed to a conceptual shift in understanding metabolic contributions to neurodegeneration. Rather than focusing exclusively on neuron–astrocyte interactions, our findings highlight the dynamic role of the vasculature in mediating metabolic effects on neuronal function.
Key outcomes include:
• Development of advanced NVU-on-a-chip technologies with integrated functional readouts.
• Demonstration that extreme hyperglycemia impairs BBB integrity and neuronal activity.
• Discovery that glucose effects are context-dependent, with moderate elevations potentially supporting recovery after injury.
• Establishment of a human-relevant platform for studying insulin signaling, metabolic stress, infection, trauma, and additional neurovascular pathologies.
Overall, this work advances a refined paradigm in which the NVU acts as a metabolic regulator translating systemic metabolic states into neuronal outcomes, opening new avenues for understanding and mitigating neurological consequences of metabolic disease.
In the last period of research, we focused on the following aims:
Platform development: – we developed a “Smart”-Organ-on-a-Chip which allows measuring the vascular functionality with spatial resolution. This work was published in Lab Chip (Renous, Noa, et al. "Spatial trans-epithelial electrical resistance (S-TEER) integrated in organs-on-chips." Lab on a Chip 22.1 (2022): 71-79, back cover)). In addition, we developed a modular chip that can transform a culture well into a chip, which saves time, money and it allows translate this technology to other labs how wish to use organs-on-a-chip technology in their lab. This work was published in APL bioengineering (Rauti, Rossana, et al. "Transforming a well into a chip: A modular 3D-printed microfluidic chip." APL bioengineering 5.2 (2021): 026103).
Covid: During the beginning of the SweetBrain project, the world pandemic started, and we joined the world effort to get more knowledge on the pandemic. To do so, we identified which of the 29 proteins which create the SARS-Cov-2 virus, has the most significant on the vasculature. We identified that 5 proteins reduce the ability of the vasculature to protect the tissues. Furthermore, we developed a computational model to predict how each one of the SARS-Cov-2 can affect the different tissues in the body. This work was published in Elife (Rauti, Rossana, et al. "Effect of SARS-CoV-2 proteins on vascular permeability." Elife 10 (2021): e69314.).
This was extremely novel, as when we published our work, there were about 100,000 papers which are Covid-related, but less then 10 on the effect of Covid on the vasculature.
This had a major impact and received a lot news coverage including national and international media (news and TV).
In addition to the work that was published, we have new unpublished data that provides insights into the effect of glucose on the endothelium, astrocytes, and neurons, which was identified by using a human-relevant advanced in vitro platform.
Dissemination and enriching the field:
The dissemination was both in scientific journals and in other means.
Scientific journal: we published three review papers that give an overview of the field. These reviews were published in Annual Reviews, APL bioengineering and Cells and Tissue research: Hajal, Cynthia, et al. "Biology and Models of the Blood–brain Barrier." Annual review of biomedical engineering 23 (2021): 359-384.; Maoz, Ben M. "Brain-on-a-Chip: Characterizing the next generation of advanced in vitro platforms for modeling the central nervous system." APL bioengineering 5.3 (2021): 030902; Maoz, Ben M., et al. "Technology-based approaches toward a better understanding of neuro-coagulation in brain homeostasis." Cell and tissue research (2021): 1-6.
Other means: I participated in more than 50 scientific conferences, and our work was promoted in the media (including TV, radio and newspapers).
Platform development: – we developed a “Smart”-Organ-on-a-Chip which allows measuring the vascular functionality with spatial resolution. This work was published in Lab Chip (Renous, Noa, et al. "Spatial trans-epithelial electrical resistance (S-TEER) integrated in organs-on-chips." Lab on a Chip 22.1 (2022): 71-79, back cover)). In addition, we developed a modular chip that can transform a culture well into a chip, which saves time, money and it allows translate this technology to other labs how wish to use organs-on-a-chip technology in their lab. This work was published in APL bioengineering (Rauti, Rossana, et al. "Transforming a well into a chip: A modular 3D-printed microfluidic chip." APL bioengineering 5.2 (2021): 026103).
Covid: During the beginning of the SweetBrain project, the world pandemic started, and we joined the world effort to get more knowledge on the pandemic. To do so, we identified which of the 29 proteins which create the SARS-Cov-2 virus, has the most significant on the vasculature. We identified that 5 proteins reduce the ability of the vasculature to protect the tissues. Furthermore, we developed a computational model to predict how each one of the SARS-Cov-2 can affect the different tissues in the body. This work was published in Elife (Rauti, Rossana, et al. "Effect of SARS-CoV-2 proteins on vascular permeability." Elife 10 (2021): e69314.).
This was extremely novel, as when we published our work, there were about 100,000 papers which are Covid-related, but less then 10 on the effect of Covid on the vasculature.
This had a major impact and received a lot news coverage including national and international media (news and TV).
In addition to the work that was published, we have new unpublished data that provides insights into the effect of glucose on the endothelium, astrocytes, and neurons, which was identified by using a human-relevant advanced in vitro platform.
Dissemination and enriching the field:
The dissemination was both in scientific journals and in other means.
Scientific journal: we published three review papers that give an overview of the field. These reviews were published in Annual Reviews, APL bioengineering and Cells and Tissue research: Hajal, Cynthia, et al. "Biology and Models of the Blood–brain Barrier." Annual review of biomedical engineering 23 (2021): 359-384.; Maoz, Ben M. "Brain-on-a-Chip: Characterizing the next generation of advanced in vitro platforms for modeling the central nervous system." APL bioengineering 5.3 (2021): 030902; Maoz, Ben M., et al. "Technology-based approaches toward a better understanding of neuro-coagulation in brain homeostasis." Cell and tissue research (2021): 1-6.
Other means: I participated in more than 50 scientific conferences, and our work was promoted in the media (including TV, radio and newspapers).
The impact of the work that we did (and published) until now was more impactful than we could expected.
Our work on Covid was one of the first papers that identified the main vascular proteins that are effected by the virus. In addition to the fact that it had a significant impact in the media, it has more than 40 citations win less then 2 years. This work provide a significant input on the disease and provides a computational model and data that was not existing until now. and scientifically.
The platforms that we developed, is the first of a kind platform that enables labs to transform their standard lab tools to Organs-on-a-Chip, and to have in situ sensors to monitor the cellular functionality.
Currently, we develop a one of a kind human model and the neurovascular unit, and we will provide, significant insights on the effect of sugar on the brain functionality, which can lead to neurodegenerative disease.
The data and insights that will be provided in this work are unprecedented, and will have a significant effect on our understanding on the effect of glucose on the brain.
Our work on Covid was one of the first papers that identified the main vascular proteins that are effected by the virus. In addition to the fact that it had a significant impact in the media, it has more than 40 citations win less then 2 years. This work provide a significant input on the disease and provides a computational model and data that was not existing until now. and scientifically.
The platforms that we developed, is the first of a kind platform that enables labs to transform their standard lab tools to Organs-on-a-Chip, and to have in situ sensors to monitor the cellular functionality.
Currently, we develop a one of a kind human model and the neurovascular unit, and we will provide, significant insights on the effect of sugar on the brain functionality, which can lead to neurodegenerative disease.
The data and insights that will be provided in this work are unprecedented, and will have a significant effect on our understanding on the effect of glucose on the brain.