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Three-dimensional-engineered bioprinted in vitro human neural stem cell self-assembling culture model constructs of Alzheimer's disease.

ABSTRACT: The pathogenic cascade of Alzheimer's disease (AD) characterized by amyloid-β protein accumulation is still poorly understood, partially owing to the limitations of relevant models without in vivo neural tissue microenvironment to recapitulate cell-cell interactions. To better mimic neural tissue microenvironment, three-dimensional (3D) core-shell AD model constructs containing human neural progenitor cells (NSCs) with 2% matrigel as core bioink and 2% alginate as shell bioink have been bioprinted by a co-axial bioprinter, with a suitable shell thickness for nutrient exchange and barrier-free cell interaction cores. These constructs exhibit cell self-clustering and -assembling properties and engineered reproducibility with long-term cell viability and self-renewal, and a higher differentiation level compared to 2D and 3D MIX models. The different effects of 3D bioprinted, 2D, and MIX microenvironments on the growth of NSCs are mainly related to biosynthesis of amino acids and glyoxylate and dicarboxylate metabolism on day 2 and ribosome, biosynthesis of amino acids and proteasome on day 14. Particularly, the model constructs demonstrated Aβ aggregation and higher expression of Aβ and tau isoform genes compared to 2D and MIX controls. AD model constructs will provide a promising strategy to facilitate the development of a 3D in vitro AD model for neurodegeneration research.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC8665263 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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Three-dimensional-engineered bioprinted in vitro human neural stem cell self-assembling culture model constructs of Alzheimer's disease.

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