A three-dimensional human neural cell culture model of Alzheimer’s disease

By Se Hoon Choi, Young Hye Kim, Matthias Hebisch, Christopher Sliwinski, Seungkyu Lee, C. D'Avanzo, Jennifer Chen, B. Hooli, Caroline Asselin, J. Muffat and 9 more. Nature, 2014

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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.

Subfields: Developmental Neuroscience, Pharmacology, Physiology

View Paper: https://www.semanticscholar.org/paper/b2503d3f0879b12f1d2ba7f848f927f16f963e6e

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Citations in the corpus

The amyloid hypothesis of Alzheimer's disease at 25 years (2016, neutral): “…biopsies of FAD subjects have been used to show first Ab accumulation and then tau alteration in the absence of overexpression (Shi et al, 2012; Choi et al, 2014; Muratore et al, 2014; Moore et al, 2015) suggesting that the lack of tangle formation in early mouse models was related to the…”
Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein (2015, neutral): “amyloid plaques and inclusionsmade ofwild-type tau (69).”
Exosome Theranostics: Biology and Translational Medicine (2018, background): “This study suggested that the excessive accumulation of amyloid-β peptide can result in Alzheimer’s disease [123].”
Induced Adult Neurogenesis plus BDNF Mimicks the Effects of Exercise on Cognition in an Alzheimer’s Mouse Model (2018, background): “Protective effects of TGF-b1 against cell death were confirmed in three-dimensional (3D) cultures of differentiated human NPCs expressing familial AD-relatedmutations (3D-FAD cells) (30).”
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019, neutral): “Importantly, this model also develops elevated phospho-tau levels and fibrillary tau aggregates, suggesting that elevated Aβ levels alone are sufficient to drive tau pathology in human neurons (Choi et al., 2014).”
Brain organoids: advances, applications and challenges (2019, background): “Although not strictly classified as organoids, human neural cultures in ECM gel or neurospheres derived from individuals with Alzheimer’s disease (AD)have been shown to recapitulateAD-like pathologies, including amyloid aggregation, hyperphosphorylated tau protein, and endosome abnormalities (Choi e”