Alzheimer’s disease (AD) affects over 43.8 million people worldwide, leading to the progressive loss of neurons and their connections (synapses). This results in memory loss, cognitive decline, and disconnection from reality, imposing a significant burden on patients and society. While various factors contribute to AD progression—ranging from genetic risks to the accumulation of extracellular Amyloid-β (Aβ) plaques, tau tangles within neurons, and changes in glial cells and blood vessels—the precise mechanisms remain unclear. For instance, Aβ plaques can accumulate years before symptoms appear and do not always lead to neurodegeneration. We hypothesize that microglia, the brain’s immune cells, play a crucial role in AD. Microglia protect and support neurons but can also prune excess synapses during early brain development. In AD, we suspect that microglia not only target Aβ plaques but also healthy synapses, contributing to neuronal loss. However, the interactions between microglia, neurons, and synapses, and how these interactions change in AD, are not well understood. Previous studies suggest that specific receptors and ligands on microglia and synapses mediate these interactions, making them potential drug targets. While some of these proteins are known to regulate synaptic pruning, others remain undiscovered. Most knowledge about microglia comes from rodent studies, but human microglia behave differently, particularly in expressing AD risk genes and responding to Aβ. To address this, we transplanted human stem cell-derived microglia into the brains of mice (xenotransplantation), allowing human microglia to develop in a living brain environment and adopt human-like behaviors, especially in response to Aβ plaques. Our main objective is to use this xenotransplantation model to identify human proteins involved in microglia-synapse interactions and determine if changes in these proteins lead to synapse loss in AD. We employ techniques like TurboID and mass spectrometry to tag and identify these proteins, creating an interactome map. This map will be a valuable resource for the microglia research field. Next, we aim to investigate how Aβ plaques affect these interactions and specifically how they influence synapse loss. This research could uncover new therapeutic targets to prevent synapse loss in AD, significantly impacting treatment strategies and improving the quality of life for AD patients. The expected impacts of this project are substantial. By elucidating the role of microglia in AD and identifying new therapeutic targets, we aim to advance treatment strategies significantly. This could lead to improved outcomes and quality of life for millions of AD patients worldwide, highlighting the project’s scale and significance.
