Early-onset familial Alzheimer’s disease mutations induce both amyloid-β and tau pathologies in differentiated human neural stem cells in 3D cultures. Although it is accepted that both aggregates of amyloid-β and neurofibrillary tangles of hyper-phosphorylated tau protein contribute to Alzheimer's disease pathology, no single model has incorporated both of these pathological events using human cells. Here, Rudolph Tanzi and colleagues find that familial Alzheimer's disease mutations in the amyloid-β precursor protein (APP) and presenilin 1 (PSEN1) genes are able to induce robust extracellular deposition of amyloid-β, including β-amyloid plaques, in a human neural stem-cell-derived three-dimensional culture system. This provides experimental validation of the amyloid hypothesis that proposes that the amyloid-β accumulation drives tauopathy in Alzheimer's disease. The cell culture system used here can be used as a platform for studying the pathogenic mechanisms of Alzheimer's disease and for drug screening. Alzheimer’s disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles1. The amyloid hypothesis of Alzheimer’s disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau2,3. However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer’s disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer’s disease, including distinct neurofibrillary tangle pathology4,5. Human neurons derived from Alzheimer’s disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles6,7,8,9,10,11. Here we report that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-β, including amyloid-β plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloid-β generation with β- or γ-secretase inhibitors not only decreased amyloid-β pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-β-mediated tau phosphorylation. We have successfully recapitulated amyloid-β and tau pathology in a single 3D human neural cell culture system. Our unique strategy for recapitulating Alzheimer’s disease pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models of other neurodegenerative disorders.
