Alzheimer's disease is the most common form of
dementia, characterized by two pathological hallmarks:
amyloid-β plaques and neurofibrillary tangles. The
amyloid hypothesis of
Alzheimer's disease posits that the excessive accumulation of
amyloid-β
peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau. 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 pathology. 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 tangles. 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.