Simple modeling of Alzheimer’s disease using human pluripotent stem cell-derived cerebral organoid technology

Abstract

Abstract Background Cerebral organoids (COs) are the most advanced in vitromodels that resemble the human brain. Use of COs as a model for human Alzheimer’s disease (AD), among other brain diseases, has recently gained attention. This study aimed to develop a human AD CO model, using normal human pluripotent stem cells (hPSCs), that recapitulates the pathological phenotypes of AD and to determine the usefulness of this model for drug screening. Methods We established AD hPSC lines from normal hPSCs by introducing genes with familial ADmutations and COs were generated using these hPSC lines. The pathological features of AD, including extensive amyloid-β (Aβ) accumulation,tauopathy, and neurodegeneration, were analyzed using enzyme-linked immunosorbent assay, Amylo-Glo staining, thioflavin-S staining, immunohistochemistry, Bielschowsky’s staining, and western blot analysis. Results AD COs showed extensive accumulation of Aβ. The levels of paired helical filament (PHF)-tau and neurofibrillary tangle (NFT)-like silver deposits were highly increased in the AD COs. The number of cells immunoreactive for cleaved caspase-3 (cCASP3) was significantly increased in AD COs. Additionally, treatment of AD COs with BACE1 inhibitor IV (a β-secretase inhibitor) and compound E (a γ-secretase inhibitor) significantly attenuated AD pathological features. Conclusion Our model recapitulates AD pathology effectively. Hence, it is a valuable platform for understanding the mechanisms underlying AD pathogenesis and can be used to test the efficacy of anti-AD drugs.