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A 3D human neural cell culture system for modeling Alzheimer's disease.

ABSTRACT: Stem cell technologies have facilitated the development of human cellular disease models that can be used to study pathogenesis and test therapeutic candidates. These models hold promise for complex neurological diseases such as Alzheimer's disease (AD), because existing animal models have been unable to fully recapitulate all aspects of pathology. We recently reported the characterization of a novel 3D culture system that exhibits key events in AD pathogenesis, including extracellular aggregation of amyloid-? (A?) and accumulation of hyperphosphorylated tau. Here we provide instructions for the generation and analysis of 3D human neural cell cultures, including the production of genetically modified human neural progenitor cells (hNPCs) with familial AD mutations, the differentiation of the hNPCs in a 3D matrix and the analysis of AD pathogenesis. The 3D culture generation takes 1-2 d. The aggregation of A? is observed after 6 weeks of differentiation, followed by robust tau pathology after 10-14 weeks.

SUBMITTER: Kim YH

PROVIDER: S-EPMC4499058 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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A 3D human neural cell culture system for modeling Alzheimer's disease.

Kim Young Hye YH Choi Se Hoon SH D'Avanzo Carla C Hebisch Matthias M Sliwinski Christopher C Bylykbashi Enjana E Washicosky Kevin J KJ Klee Justin B JB Brüstle Oliver O Tanzi Rudolph E RE Kim Doo Yeon DY

Nature protocols 20150611 7

Stem cell technologies have facilitated the development of human cellular disease models that can be used to study pathogenesis and test therapeutic candidates. These models hold promise for complex neurological diseases such as Alzheimer's disease (AD), because existing animal models have been unable to fully recapitulate all aspects of pathology. We recently reported the characterization of a novel 3D culture system that exhibits key events in AD pathogenesis, including extracellular aggregati ...[more]

PMID: 26068894

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Project description:Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-? plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-? 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-?-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-? species and phosphorylated tau but did not demonstrate amyloid-? plaques or neurofibrillary tangles. Here we report that FAD mutations in ?-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-?, including amyloid-? 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-? generation with ?- or ?-secretase inhibitors not only decreased amyloid-? pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-?-mediated tau phosphorylation. We have successfully recapitulated amyloid-? 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.

Dataset Information

A 3D human neural cell culture system for modeling Alzheimer's disease.

Publications

A 3D human neural cell culture system for modeling Alzheimer's disease.

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