Development of human 3D organoid model of Alzheimer's disease

forthcoming

Alzheimer’s disease (AD) is the leading cause of dementia, affecting over 50 million people worldwide. Characterized by memory loss, cognitive decline, and the formation of amyloid-β plaques and neurofibrillary tangles, AD presents a significant global health burden. Current AD models, particularly in mice, fail to accurately represent the sporadic form of human AD, limiting the translation of research into effective treatments. Human-induced pluripotent stem cells (hiPSCs) offer a promising alternative for creating in vitro models, but these often lack key features of AD pathology and immune cell interactions. This project aims to develop a 3D organoid model for sporadic AD. We will use nanoparticles as nucleation seeds to facilitate amyloid aggregation from AD patient brain extracts, allowing a more faithful representation of AD pathology. By incorporating microglia into the model, we aim recapitulate human-specific microglial states in AD. By analyzing organoids with and without microglia, we will be able to investigate whether and how microglia contribute to initiation and progression of AD-related pathology, thus providing insights into this so far unanswered question in the field. We will compare all obtained readouts to idiopathic normal pressure hydrocephalus patient brain biopsies, that contain early AD-related pathology, thus verifying that our model is able to recapitulate features of human AD brain. This innovative approach will address the limitations of current models by integrating both neuronal and immune components, offering a more comprehensive platform for studying AD and testing potential therapies. Overall, the project has the potential to advance our understanding of AD mechanisms and contribute to the development of more effective treatments.