Periodic Reporting for period 1 - XenoMicrogliaAD (Deciphering the microglia-neuron interactions in human Alzheimer's disease)
Periodo di rendicontazione: 2023-01-01 al 2025-06-30
Microglia are special cells in the brain that play a key role in Alzheimer’s disease (AD). Even though a lot of research has been done to understand how microglia respond to AD, we still do not fully know how they interact with other brain cells and how they contribute to damage in brain cells. Our main goal is to explore how human microglia affect brain cell connections and damage in a living organism. Human microglia are different from those in mice, especially regarding certain genes linked to Alzheimer’s, which makes it important to study them in humans. Some behaviours of these cells are also hard to study in lab dishes because they involve complicated interactions with other cells. In XenoMicrogliaAD, we will use a new model that we developed, which allows us to transplant human microglia into mouse systems, and examine how they affect brain health. Specifically, we will look at two main ways microglia might harm brain cells: by removing connections between cells and by releasing substances that can lead to cell damage. To do this, we will use advanced techniques to study how human microglia interact with brain cells and what substances they produce in the context of Alzheimer’s disease. The project will help map how microglia interact with synapses (connections between brain cells) in both healthy brains and those affected by Alzheimer’s disease. It will also explore the interactions between human microglia and brain cells in living systems, and identify the specific substances produced by these microglia in Alzheimer’s disease. This research will be the first to deeply investigate the role of human microglia in Alzheimer’s disease at this level of detail, potentially leading to new treatments and ways to detect and tackle the disease.
Microglia are special immune cells in the brain that play a key role in Alzheimer’s disease (AD). However, we still do not fully understand how they interact with other brain cells and how they contribute to the damage seen in AD. Our goal is to investigate how human microglia contribute to problems with brain connections and cell damage.
Objective 1: We want to explore how human microglia interact with nerve connections in the brain using a new model we created where we can transplant human microglia into mice. We are working on mapping these interactions in both healthy and AD-affected brains. At first, we planned to use a specific method to study these interactions, but we faced challenges that made us change our approach. Now, we are looking at how microglia interact by focusing specifically on proteins found on their surfaces. This way, we can gather detailed information about potential targets for new treatments.
Objective 2: We want to learn more about how human microglia and nerve cells interact in Alzheimer’s by transplanting both into the brains of mice. We have set up a technique to create neural precursor cells (which can develop into nerve cells) from human stem cells. We confirmed these cells can grow and integrate into the mouse brain. Our next step is to combine both human microglia and neural cells in this model to further investigate their interactions in the context of AD.
Objective 3: We are developing a method to trace the proteins produced by transplanted human microglia, specifically looking for those related to inflammation in AD. We have created cell lines that help us label the proteins made by microglia. We have validated our methods and confirmed that our labelling works well. We also conducted experiments where we transplanted the modified microglia into mice, confirming that they integrated well and produced the labeled proteins.
Objective 1: We want to explore how human microglia interact with nerve connections in the brain using a new model we created where we can transplant human microglia into mice. We are working on mapping these interactions in both healthy and AD-affected brains. At first, we planned to use a specific method to study these interactions, but we faced challenges that made us change our approach. Now, we are looking at how microglia interact by focusing specifically on proteins found on their surfaces. This way, we can gather detailed information about potential targets for new treatments.
Objective 2: We want to learn more about how human microglia and nerve cells interact in Alzheimer’s by transplanting both into the brains of mice. We have set up a technique to create neural precursor cells (which can develop into nerve cells) from human stem cells. We confirmed these cells can grow and integrate into the mouse brain. Our next step is to combine both human microglia and neural cells in this model to further investigate their interactions in the context of AD.
Objective 3: We are developing a method to trace the proteins produced by transplanted human microglia, specifically looking for those related to inflammation in AD. We have created cell lines that help us label the proteins made by microglia. We have validated our methods and confirmed that our labelling works well. We also conducted experiments where we transplanted the modified microglia into mice, confirming that they integrated well and produced the labeled proteins.
We have created different collections of induced pluripotent stem cells (iPSCs) that have been modified to use a technology called TurboID, which helps us study the proteins and substances produced by microglial cells. This technology can also be applied to other cell types if there are available methods for their development. We have developed the necessary tools, including plasmids and viral constructs, both internally at VIB and with outside collaborators. The research community sees this technology as a valuable way to explore cell biology. While we have not leverage these technologies for valorisation yet, our project is focused on practical applications, so we are likely to discover new biomarkers or treatment strategies in the coming years.