MICROGLIA INTEGRATION ACCELERATES PATHOLOGICAL PHENOTYPES IN A HUMAN MULTICELLULAR BRAIN ORGANOID MODEL OF ALZHEIMER’S DISEASE (AD HMBO)

Alzheimer's disease (AD), the predominant cause of dementia in the elderly, is neuropathologically characterized by the presence of amyloid-beta (Aβ) plaques and neurofibrillary tangles in the brain. Increasing evidence supports a central role of the inflammatory component driven by microglia cells (MC) in AD pathogenesis and highlights the importance of human species-specific factors to accurately model the disease. Recent data suggests that MC could contribute to Aβ plaque formation at early stages of the pathology in mouse models (Baligács et al., 2024). However, their role in a fully human genetic background remains poorly understood.
Here, we generated human pluripotent stem cell (hPSC)-derived MC and examined their responses to AD-related pathology both in monoculture and within a human multicellular brain organoid model (hmBO) carrying the familial AD-associated London mutation within the APP gene.
MC exposed to soluble Aβ peptides and to fibrillar Aβ resulted in increased MC recruitment, clustering, and phagocytic activity, demonstrating that hPSC-derived MC functionally respond to Aβ similarly to microglia in the human AD brain. hPSC-London hBOs without MC recapitulate the formation of small, non-fibrillar Aβ aggregates and Tau hyperphosphorylation without significant cell death. Notably, the introduction of hPSC-derived MC (AD hmBOs) led to their active recruitment to Aβ deposits and resulted in a significant increase in both the number and size of Aβ aggregates, alongside alterations in Tau phosphorylation levels.
Together, these results establish hmBOs as a valuable human platform for investigating microglia-driven mechanisms in neurodegenerative diseases, such as AD.