Organoids as a Human Brain Model for Alzheimer’s Disease

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid beta (Aβ) plaques, associated immune system dysregulation, and progressive loss of memory and cognitive function. Modeling AD pathology in human-relevant systems is critical for understanding disease mechanisms and developing therapeutic strategies. While traditional models provide valuable insights, they fail to recapitulate the human-specific cellular and molecular interactions observed in AD, particularly the interplay between microglia, interneurons, and Aβ plaques. This study aimed to establish a physiologically relevant 3D human brain organoid model incorporating microglia and interneurons to investigate AD pathology. Using human-induced pluripotent stem cells (hiPSCs), brain organoids were generated and treated with Aβ brain extracts and nanoparticles. Nanoparticles were tested as a potential delivery system for distributing Aβ brain extracts uniformly within organoids. Confocal microscopy was employed to analyze Aβ plaques, interneurons, and the incorporation of microglia. Imaging analysis successfully visualized Aβ plaques and interneurons, validating the model for studying AD-like pathology. However, microglial incorporation was not detectable under the experimental conditions, indicating a limitation in the protocol. It remains unclear whether this issue arose from the immunohistochemistry (IHC) protocol or the method used for microglial incorporation into the organoids, emphasizing the necessity for further investigations to refine these processes and enhance the model's reliability. Additionally, Aβ plaques were not observed in organoids treated with nanoparticles alone, suggesting that nanoparticles might not induce Aβ aggregation independently. Nanoparticles facilitated Aβ dispersion within the organoid matrix; however, the anticipated increase in plaque density was not observed, indicating potential inefficiencies in nanoparticle-mediated delivery. This study contributes to ongoing efforts to develop human-relevant models for investigating AD pathology. This study highlights the potential of human-relevant models for AD pathology while emphasizing the need for continued research to optimize protocols and improve model reliability.