Recapitulation of plaque formation, tau pathology, and neurodegeneration in a human 3D matrix model of Alzheimer’s disease

This study aims at implementing a 3D cell culture model of Alzheimer's disease (AD). To that end we engineered human induced pluripotent stem cell (iPSC)-derived neural stem cells to conditionally overexpress FAD mutant APP and PSEN1 variants. After differentiation in 3D basement membrane matrices, cultures exhibited increased Aβ₄₂ and Aβ₄₀ levels and a highly pathogenic shift of the Aβ_42/40 ratio. Typical AD phenotypes such as amyloid deposition and tau pathology were observed alongside impaired mitochondrial integrity and neuronal damage. Pathophenotypes were ameliorated by γ-secretase inhibition, confirming amyloid toxicity as main driver of AD pathology. iPSC-derived microglia added to the cultures engulfed Aβ and apoptotic cells, underscoring the modularity of this experimental system. We expect our model to provide a useful tool for assessing the impact of amyloid reduction on downstream AD pathologies such as mitochondrial dysfunction, neuroinflammation, and neurodegeneration, in particular in light of recent progress in the development and use of amyloid-targeting drugs.